1 Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, 2 Department of Nursing, Warren Grant Magnuson Clinical Center, 3 Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892 and 4 Contraception & Reproductive Health Branch, National Institute of Child Health and Human Development, Executive Bldg, Rm 8B07, 6100 Executive Blvd MSC 7510, Bethesda, MD 20892-7510, USA
5 Present address: 650 Pennsylvania Ave SE, Suite 50, Washington, DC 20003, USA.
6 Current address: 12 Wexford Glenn, Pittsford, NY 14534, USA.
7 Present address: 3 Chevy Chase Circle, Chevy Chase, MD 20815, USA
8 To whom correspondence should be addressed. e-mail: NiemanL{at}nih.gov
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Abstract |
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Key words: CDB-2914/menses/normally cycling women/progesterone receptor modulator
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Introduction |
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Despite the therapeutic promise of mifepristone, its undesirable side-effects related to glucocorticoid antagonism have led to efforts to develop other compounds with more pure antiprogestational action. Other structurally similar compounds with an 11-aromatic substitution and antiprogestational activity (Teutsch and Philibert, 1994
) have been synthesized, but few have entered clinical trials and none are commercially available. Thus, further development of such agents is desirable.
CDB-2914, 17-acetoxy-11
-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione (Figure 1), is a 19-nor steroid that is structurally similar to mifepristone. In vitro, CDB-2914 binds competitively to the progesterone, glucocorticoid and androgen receptors, but has minimal affinity for the estrogen or mineralocorticoid receptors (D.Blithe, unpublished data, IND 49,381; Cook et al., 1994
; Wagner et al., 1999
; Attardi et al., 2002
). The compound has antiprogestational activity in rats, rabbits and monkeys, with additional antiglucocorticoid and antiandrogen activity at doses
50 times higher than those needed for antiprogestational activity (Tarantal et al., 1996
; Reel et al., 1998
; Hild et al., 2000
). In women, a single mid-follicular phase dose of CDB-2914 (compared with placebo, 10, 50 or 100 mg) caused dose-dependent inhibition of folliculogenesis and steroidogenesis (Stratton et al., 2000
). However, its effects in the luteal phase have not been examined. This trial was designed to evaluate the safety, adverse effects, pharmacokinetics and biological activity of single escalating doses of CDB-2914 in the luteal phase of normally cycling women not at risk for pregnancy.
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Subjects and methods |
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Study design
The study protocol (95-CH-0168) was approved by the Institutional Review Board of the National Institute of Child Health and Human Development (NICHD). After giving informed written consent, all participants underwent a history, physical examination and routine laboratory analysis. Women used an in-home test (OvuquickTM; Quidel, USA) to detect the urinary LH surge and documented this date as well as basal body temperature, vaginal bleeding or spotting, and any constitutional symptoms on a menstrual calendar.
During the first (pre-treatment) cycle, participants reported to the clinic 68 days after detection of urinary LH, for measurement of serum progesterone. Women lacking an LH surge or a luteal phase progesterone level were excluded.
During the second (treatment) cycle, participants were admitted to the Clinical Center for administration of either placebo or CDB-2914 at one of five doses (1, 10, 50, 100 or 200 mg) on luteal day 68. After an overnight fast, the test compound was given between 08:00 and 10:00 h, and women remained at bed rest for 24 h. Blood samples were drawn at 15 and 1 min before and 15, 30, 60, 90 min, 2, 3, 4, 6, 8, 12, 16, 24 and 36 h after administration of the test compound for cortisol, ACTH and CDB-2914 measurements. Blood was drawn at 0, 4, 8, 12 and 24 h for FSH, LH, estradiol, progesterone, prolactin and renin measurements. After discharge at 36 h, women returned daily until vaginal bleeding commenced for measurement of vital signs and serum estradiol and progesterone levels. Women collected urine for three consecutive days following CDB-2914 administration. Urinalysis, haemogram (CBC), blood chemistry, kidney and liver function tests were obtained at baseline and on days 1, 2 and 7 to monitor for signs of toxicity. Serum thyroxine was measured at baseline and 7 days after treatment.
The initial CDB-2914 dose of 1 mg was increased incrementally following the absence of adverse findings at each dose level. The six placebo doses were interspersed randomly by the pharmacy within the active compound groups. Within each dosage group, neither participants nor investigators were aware of the identity of the agent administered.
In the third (post-treatment) cycle, women returned to the clinic on luteal day 68 for measurement of serum progesterone to document normal luteal function.
CDB-2914 and other steroids
Pure crystalline CDB-2914 and its putative metabolites, and the 3-carboxymethyloximebovine serum albumin (BSA) and 3-carboxymethyloximehistamine conjugates of CDB-2914 were synthesized by the Southwest Foundation for Biomedical Research (USA) under contract N01-HD-1-3137 to the Contraception and Reproductive Health Branch, NICHD, and were a gift from that branch (Rao et al., 1999). The Clinical Center Pharmaceutical Development Service sieved the powder with a 125 mm mesh sieve and formulated gelatin capsules containing either 1, 10, 50, 100 or 200 mg of CDB-2914, or inert powder (AvicelTM microcrystalline cellulose; FMC Corp., USA). Mifepristone was purchased from SigmaAldrich Company (USA).
Hormone and CDB-2914 assays
All hormone measurements except serum thyroid-stimulating hormone (TSH) were performed at Covance Laboratories (USA), using established assays. Plasma FSH and LH (Odell et al., 1967), prolactin, renin and cortisol (Chrousos et al., 1984
) were measured using direct radioimmunoassay, and ACTH (Chrousos et al., 1984
), estradiol (Jiang et al., 1969
; Abraham et al., 1972
) and progesterone (DeVilla et al., 1972
) were measured by radioimmunoassay after extraction. Urinary free cortisol (UFC) was measured by radioimmunoassay (Nichols Institute Diagnostics, USA). Serum TSH was measured at the Clinical Center using a standard second generation assay (Diagnostic Products Co., USA).
CDB-2914 was measured in serum by radioimmunoassay using iodinated CDB-2914 tracer and rabbit antisera against a 3-carboxymethyloximeBSA conjugate of CDB-2914, as previously described (Larner et al., 2000). BIOQUAL, Inc. (USA) performed the assays under NICHD contract N01-HD-6-3259. The N-mono and N-didemethylated putative metabolites of CDB-2914 showed 76 and 59% cross-reactivity with antiserum 67192 respectively (Larner et al., 2000
). Thus, results from this assay should be considered to represent the parent compound and possible metabolites of unknown biological potency in people. Progesterone, mifepristone, estradiol, estrone, cortisol, testosterone, and the putative 17
-hydroxy metabolite of CDB-2914 exhibited cross-reactivities with antiserum 67192 of <1%.
The usable range of the CDB-2914 standard curve was 1 to 400 pg/tube with a mid-point of 30 ± 2 pg/tube (mean ± SE: n = 10) and a mean slope of 0.91 ± 0.03 (n = 10). The average limit of detection was 1 ± 0.1 pg/tube. The recovery of CDB-2914 from low, mid- and high concentration quality control human serum pools run with each assay averaged 100 ± 8% (n = 3). Selected serum samples from three of the study subjects were assayed for CDB-2914 and immunoreactive metabolites over a series of dilutions. Using a four-parameter logistic plot of percentage bound versus log10 concentration, the diluted serum samples behaved in a linear and parallel fashion as compared with the CDB-2914 standard curve. The mean slope of the curves for the diluted serum samples (n = 3) was 0.83 (95% Cl, 0.72 to 0.94).
The same preparation of [125I]CDB-2914 was used in all assays. CDB-2914 and its immmunoreactive metabolites were extracted with methanol from serum samples and assayed as described using a 1:510 000 final antiserum dilution. The inter- and intra-assay coefficients of variation were 7.7 and 7.7% (n = 10) respectively, as calculated from CDB-2914 spiked human serum quality control samples run for each assay.
High performance liquid chromatography (HPLC) assay
CDB-2914 serum concentrations were determined at the 100 and 200 mg doses by HPLC, and were evaluated at these doses in five and four subjects respectively. In brief, steroids were extracted from 0.25 ml serum by vortexing it with 1 ml acetonitrile for 30 s. The samples were centrifuged at 10 000 rpm for 5 min at 4°C and the supernatant was transferred to a glass tube and evaporated to dryness. The sample was reconstituted with 200 µl mobile phase and vortexed. A total of 150 µl was injected into a Water Nova-Pak C18 column and eluted at 1 ml/min with a gradient mobile phase containing 0.02 mmol/l ammonium acetate (solvent A) and acetonitrile (solvent B). A gradient profile was started with 50% A and 50% B. At 8 min, A/B ratio was gradually changed so that by 11 min into the run, the concentration of solvent B was 70%. This ratio was maintained until 14 min into the run where solvent concentration was returned to 50%. The total run time was 21 min. CDB-2914 had an eluting time of 12 min and was detected from UV absorbance at 303 nm. The assay had a lower limit of quantification of 25 ng/ml. The three putative metabolites of CDB-2914 (the 17-hydroxy, monodemethylated and didemethylated analogues) were added to sera, and were detected at different eluting times (3.2, 6.1, 6.7 min) so that there was no interference with the peak of the parent compound (Figure 2). We did not assess the presence of these metabolites in subjects sera. The mean extraction recovery of CDB-2914 was 95%. The intra- and inter-assay coefficients of variation were 1.4 and 3.6%.
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A physiological concentration of each purified protein, 12.2 µmol/l human 1-acid glycoprotein (hAGP; orosomucoid), 606 µmol/l human serum albumin (HSA) or 8.9 µmol/l purified human gamma-globulin, in phosphate-buffered saline (PBS, pH 7.4) containing 5% ethanol was placed in one chamber of the equilibrium dialysis unit and a 5 nmol/l solution of [3H]progesterone, [3H]CDB-2914 or [3H]mifepristone in PBS/5% ethanol was placed in the units second chamber. Incubations were carried out as previously described (Larner et al., 2000
).
Analysis of data
Menstrual cycle length was defined as days from the first day of bleeding until and including the day before the next menses/endometrial bleeding. Follicular phase length was defined as the days from the first day of bleeding until and including the first day of detectable urinary LH. The luteal phase length was defined as days after the urinary LH surge until the day before the next menses/endometrial bleeding.
Early endometrial bleeding was defined as bleeding per vagina that occurred earlier than that seen in the pre-treatment cycles, all of which had a luteal phase >12 days. Functional luteolysis was defined as a decreasing estradiol value to <180 pmol/l over 3 days, and either a concurrent decrease of progesterone to <16 nmol/l, or decreasing progesterone values over
3 days, reaching a nadir
50% of the baseline.
Data are given as mean ± SE except where noted. To analyse the data statistically, we used the computer program StatView (version 4.51; Abacus Concepts Inc., USA) on a Power Computing computer to perform analysis of covariance for repeated measurements of the same variable, or to compare variables across groups. P < 0.05 was considered significant.
Radioimmunoassay data were analysed by the RiaSmartTM four parameter sigmoidal computer program (RiaSmartTM Immunoassay Data Reduction program; Packard Instrument Co., USA).
The pharmacokinetic data were analysed by both non-compartmental and compartmental analysis. Pharmacokinetic parameters for CDB-2914 were calculated using non-compartmental analysis. The terminal elimination rate constant (Ke) of CDB-2914 was determined from linear regression analysis for the HPLC data only because of the apparent measurement of metabolites and parent compounds by the radioimmunoassay. Apparent volume of distribution (Vd) was determined as: Vd = CL/Ke. The serum elimination half-life (t1/2) was calculated as: t1/2 = 0.693/Ke. The area under the serum concentrationtime curve (AUC) from HPLC data was calculated using the linear trapezoidal method from time zero to the last concentration time-point obtained and extrapolated to infinity by dividing the last concentration by the terminal elimination rate constant. For data from radioimmunoassay, AUC was calculated using the linear trapezoidal method from time zero to 72 h. CDB-2914 oral clearance was determined as CL = dose/AUC. For compartmental analysis, ADAPT II version 4 (Biomedical Stimulation Resource, University of Southern California, USA) was used (DArgenio and Schumitzky, 1979). Model selection was determined using Akaikes Information Criterion, Schwartz criterion and visual examination of the fitted versus observed concentrations (Yamaoka et al., 1978
).
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Results |
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Each woman had only one episode of endometrial bleeding after CDB-2914 or placebo. Women with concomitant functional luteolysis and bleeding characterized the duration (4.9 ± 0.2 days, range 38) and quality of bleeding as normal. However, women with early endometrial bleeding without concomitant functional luteolysis had a significantly longer duration of bleeding (10.3 ± 2.1 days, range 520; P < 0.001 versus women with concomitant luteolysis), characterized by the subjects as having more spotting at the beginning and ending than the usual menses.
The follicular phase length in the post-treatment cycle, when defined by the onset of endometrial bleeding, was significantly longer in women with early bleeding and no functional luteolysis compared with women who had concurrent luteolysis and bleeding (17.3 ± 1.1 versus 14.3 ± 0.5 days, P < 0.01), presumably because of the dissociation between bleeding and functional luteolysis. Post-treatment cycles were ovulatory in all women.
CDB-2914 had no apparent effect on the hypothalamicpituitaryadrenal axis or other endocrine function: there was no statistically significant change in urinary free cortisol, plasma renin activity, or plasma prolactin, thyroxine, LH or FSH levels following CDB-2914 administration, as compared with baseline. The diurnal variation of cortisol (0800 h: 330 ± 20 nmol/l versus 2000 h: 85 ± 8 nmol/l, P < 0.0001; no dose effect) remained intact during the 24 h immediately following CDB-2914 administration. There was no difference in urinary cortisol excretion between groups, either 012, 1224 or 2448 h after test agent administration, and no difference between the groups in plasma ACTH or cortisol at any time-point; there were no clinical signs of adrenal insufficiency.
CDB-2914 was well tolerated and there was no abnormality of CBC, hepatic, renal or blood chemistries after the agent. Subjectively, one woman felt warm 4 h after a 10 mg dose, and one woman developed a rash on her arm and abdomen the day after a 100 mg dose. Both reactions were mild and self-limited and considered possibly related to the agent.
Clinical pharmacology
At equilibrium, [3H]CDB-2914, [3H]mifepristone and [3H]progesterone bound to human acid glycoprotein (hAGP) (58, 92 and 9% respectively) and human serum albumin (12, 84 and 63% respectively) but not to the negative control, human gamma globulin. At equilibrium, 46% of the [3H]CDB-2914 and 90% of the [3H]mifepristone were bound to proteins in the 10-fold diluted pre-treatment serum sample. These results support the hypothesis that in-vivo binding to hAGP may influence the bioavailability and pharmacokinetics of CDB-2914.
The pharmacokinetic parameters for CDB-2914 derived from the radioimmunoassay and HPLC assays are summarized in Table III. Radioimmunoassay-measurable CDB-2914/metabolite levels were detected in all women receiving active compound. A two-compartment model best characterized the HPLC data. For the radioimmunoassay data, the maximum concentration (Cmax) and AUC of CDB-2914 increased linearly as the dose increased. At doses >100 mg, Cmax did not increase further. For the HPLC data, only samples at doses of 100 and 200 mg were analysed because of the low concentrations at other doses. The serum elimination half-life was similar at both doses (100 mg: 1.5 ± 0.26 h versus 200 mg: 2.03 ± 1.12 h). The concentration-time profiles for patients analysed by both methods showed similar temporal trends, but the concentrations were significantly lower for the HPLC data compared with those of the radioimmunoassay (Figure 4 top). Tmax was not significantly different across dose groups or methods. The AUC values obtained from the HPLC method at 0infinity only accounted for 8.8 and 12.2% of the radioimmunoassay data at 072 h (100 and 200 mg dose levels respectively). The HPLC assay was specific for CDB-2914, as all three hypothesized metabolites were identified in spiked sera as discrete peaks apart from CDB-2914. These results suggest that the radioimmunoassay method detected both parent compound and metabolites.
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Discussion |
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The endometrial effects of CDB-2914 are similar to those of mifepristone, which induces uterine bleeding within 72 h of mid-luteal administration by acting directly on the endometrium to inhibit progesterone activity (Schaison et al., 1985; Shoupe et al., 1987
; Garzo et al., 1988
; Nieman and Loriaux, 1988
). The data from this study suggest that CDB-2914 and mifepristone are roughly equivalent in this regard. At 200 mg (
34 mg/kg), CDB-2914 consistently caused early endometrial bleeding. By contrast, the minimal luteal phase dose of mifepristone needed to induce endometrial bleeding consistently has not been established. Single doses of 50 mg induced bleeding in four out of four women (Shoupe et al., 1987
) in one study but a single dose of 5 mg/kg was not consistently effective in another (Nieman and Loriaux, 1988
) and four daily doses of 50 mg were only 80% effective in another study (Schaison et al., 1985
). Both agents may cause luteolysis. Luteolysis occurred in 60% of women receiving mifepristone, 100 mg for 4 days (Schaison et al., 1985
), and in all women at a single dose of 10 mg/kg (
600 mg) (Nieman and Loriaux, 1988
). The threshold dose for consistently achieving this effect was not reached in this study of CDB-2914 up to 200 mg.
Women who experienced early endometrial bleeding without functional luteolysis had a longer duration of bleeding after CDB-2914. Two had a dramatic increase in length of bleeding in the treatment cycle (15 and 20 days). In these women, the induced early bleeding had not stopped at the time of spontaneous luteolysis (around luteal phase day 13), so that the menstruation associated with luteolysis caused an apparent lengthening of bleeding.
The physiological effect of CDB-2914 probably depends on its metabolism, the biological activity of its metabolites, and the variable binding of the compounds to plasma proteins. The serum levels of CDB-2914 and immunoreactive metabolites detected by radioimmunoassay, both peak and AUC, were higher than those detectd by HPLC, which was specific for CDB-2914. The difference between these two methods suggests that high circulating levels of CDB-2914 metabolites are present. These metabolites presumably affect the overall antiprogestational and antiglucocorticoid activity of orally administered CDB-1914. The relative contribution of CDB-2914 metabolites to biological activity has not been determined.
Specific protein binding of CDB-2914 was demonstrated for 1 acid glycoprotein (orosomucoid), with less binding to albumin. These results in women are similar to previous data derived from rhesus monkeys (Larner et al., 2000
). CDB-2914 binding to orosomucoid was less than that of mifepristone, which may account for the longer half-life of mifepristone (Heikinheimo, 1997
). Issues of pharmacokinetics and bioavailability of CDB-2914 and its metabolites must await additional studies with sufficiently sensitive and specific assays for the parent compound and putative metabolites.
None of the antiprogestins in clinical trials have had pure antiprogestin effects. Their antiglucocorticoid activity occurs only at doses higher than those for antiprogestational activity and is normally overcome by an intact hypothalamicpituitaryadrenal axis (Nieman and Loriaux, 1988; Laue et al., 1990
; Bertagna et al., 1997
). However, even after a single dose, mifepristone reduces the amount of REM sleep (Wiedemann et al., 1998
), and is associated with asthenia, headache, malaise, dizziness and muscle pain (Dubois et al., 1986
; Shoupe et al., 1987
; Couzinet et al., 1990
). Data from this clinical trial suggest that single doses of CDB-2914 may be tolerated at least as well as mifepristone, with minimal side-effects.
Chronic administration of mifepristone to a patient with Cushings syndrome at daily doses of up to 25 mg/kg was well tolerated (Nieman et al., 1985). However, in healthy individuals or patients without hypercortisolism, chronic administration of mifepristone at daily doses of
200 mg has been reported to cause skin exanthem, endometrial hyperplasia and symptoms of adrenal insufficiency requiring glucocorticoid replacement (Klijn et al., 1989
; Laue et al., 1990
; Lamberts et al., 1991
; Bertagna et al., 1994
; Perrault et al., 1996
; Newfield et al., 2001
; Pomara et al., 2002
). However, one study using a daily dose of 200 mg characterized the fatigue as mild (Grunberg et al., 1991
) and others using a daily dose of
50 mg did not report any adverse effects (Croxatto et al., 1993
; Kettel et al., 1996
). Collectively, these data suggest that dose, duration and perhaps individual-specific factors influence whether side-effects occur. The presence of these undesirable side-effects has spurred a search for agents with a higher antiprogestin:antiglucocorticoid activity ratio. In this regard, CDB-2914 had no apparent clinical or biochemical antiglucocorticoid activity in this study. At the doses used it is not possible to determine whether CDB-2914 had a high antiprogestin:antiglucocorticoid activity, or whether the doses used were too low to evaluate effects on the pituitaryadrenal axis.
The information on the effects of CDB-2914 from this study supports continued clinical investigation of the agent as a promising compound with selective antiprogestin activity. Single oral doses of 1200 mg of CDB-2914 were well tolerated and without apparent toxicity, and had a dose-dependent antiprogestational effect on the mid-luteal endometrium. Further studies are needed to determine the effects on the ovary and the endometrium during chronic administration. Such data will help determine the therapeutic usefulness of CDB-2914 in clinical medicine.
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FOOTNOTES |
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References |
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Attardi, B.J., Burgenson, J., Hild, S.A., Reel, J.R. and Blye, R.P. (2002) CDB-4124 and its putative monodemethylated metabolite, CDB-4453, are potent antiprogestins with reduced antiglucocorticoid activity: in vitro comparison to mifepristone and CDB-2914. Mol. Cell. Endocrinol., 188, 111123.[CrossRef][ISI][Medline]
Bertagna, X. (1997) Pituitary-adrenal response to RU 486 in man. Psychoneuroendocrinology, 22 (Suppl. 1), S51S55.[CrossRef][ISI][Medline]
Bertagna, X., Escourolle, H., Pinquier, J.L., Coste, J., Raux-Demay, M.C., Perles, P., Silvestre, L., Luton, J.P. and Strauch, G. (1994) Administration of RU 486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation. J. Clin. Endocrinol. Metab., 78, 375380.[Abstract]
Chrousos, G.P., Schulte, H.M., Oldfield, E.H., Gold, P.W., Cutler, G.B., Jr and Loriaux, D.L. (1984) The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushings syndrome. N. Engl. J. Med., 310, 622626.[Abstract]
Cook, C.E., Lee, Y.W., Wani, M.C., Fail, P.A. and Petrow, V. (1994) Effects of D-ring substituents on antiprogestational (antagonist) and progestational (agonist) activity of 11 beta-aryl steroids. Hum. Reprod., 9 (Suppl. 1), 3219.[Abstract]
Couzinet, B., LeStrat, N., Silvestre, L. and Schaison, G. (1990) Late luteal administration of the antiprogesterone RU 486 in normal women: effects on the menstrual cycle events and fertility control in a long-term study. Fertil. Steril., 54, 10391044.[ISI][Medline]
Croxatto, H.B., Salvatierra, A.M., Croxatto, H.D. and Fuentealba, B. (1993) Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle. Hum. Reprod., 8, 201207.[Abstract]
DArgenio, D.Z. and Schumitzky, A. (1979) A program package for simulation and parameter estimation in pharmacokinetic systems. Comput. Programs Biomed., 9, 115134.[CrossRef][ISI][Medline]
DeVilla, G.O., Jr, Roberts, K., Wiest, W.G., Mikhail, G. and Flickinger, G. (1972) A specific radioimmunoassay of plasma progesterone. J. Clin. Endocrinol. Metab., 35, 458460.[ISI][Medline]
Dubois, C., Ulmann, A. and Baulieu, E. (1986) Contragestion with late luteal administration of RU 486 (Mifepristone). Fertil. Steril., 50, 595596.
Gaillard, R.C., Riondel, A., Muller, A.F., Hermann, W. and Baulieu, E.E. (1984) RU486: A steroid with antiglucocorticoid activity that only disinhibits the human pituitaryadrenal system at a specific time of the day. Proc. Natl Acad. Sci. USA, 81, 38793882.[Abstract]
Garzo, V.G., Liu, J., Ulmann, A., Baulieu, E. and Yen, S.S. (1988) Effects of an antiprogesterone (RU486) on the hypothalamichypophysealovarianendometrial axis during the luteal phase of the menstrual cycle. J. Clin. Endocrinol. Metab., 66, 508517.[Abstract]
Grunberg, S., Weiss, M., Spitz, I., Ahmadi, J., Sadun, A., Russell, C.A., Lucci, L. and Stevenson, L.L. (1991) Treatment of unresectable meningiomas with the antiprogesterone agent Mifepristone. J. Neurosurg., 74, 861866.[ISI][Medline]
Heikinheimo, O. (1997) Clinical pharmacokinetics of mifepristone. Clin. Pharmacokinet., 3, 717.
Heikinheimo, O., Ranta, S., Grunberg, S., Lahteenmaki, P. and Spitz, I.M. (1997) Alterations in the pituitarythyroid and pituitaryadrenal axesconsequences of long-term mifepristone treatment. Metabolism, 46, 292296.[CrossRef][ISI][Medline]
Heikinheimo, O., Ranta, S., Grunberg, S. and Spitz, I.M. (2000) Alterations in sex steroids and gonadotropins in post-menopausal women subsequent to long-term mifepristone administration. Steroids, 65, 831836.[CrossRef][ISI][Medline]
Hild, S.A., Reel, J.R., Hoffman, L.H. and Blye, R.P. (2000) CDB-2914: anti-progestational/anti-glucocorticoid profile and post-coital anti-fertility activity in rats and rabbits. Hum. Reprod., 15, 822829.
Jiang, N.S. and Ryan, R.J. (1969) Radioimmunoassay for estrogens: a preliminary communication. Mayo Clin. Proc., 44, 461465.[ISI][Medline]
Kettel, L.M., Murphy, A.A., Morales, A., Ulmann, A., Baulieu, E.E. and Yen, S. (1996) Treatment of endometriosis with the antiprogesterone Mifepristone. Fertil. Steril., 65, 2328.[ISI][Medline]
Klijn, J.G., de Jong, F.H., Bakker, G.H., Lamberts, S.W., Rodenburg, C.J. and Alexieva-Figusch, J. (1989) Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Res., 49, 28512856.[Abstract]
Klijn, J.G., Setyono-Han, B. and Foekens, J.A. (2000) Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer. Steroids, 65, 825830.[CrossRef][ISI][Medline]
Lamberts, S.W., Koper, J.W. and de Jong, F.H. (1991) The endocrine effects of long-term treatment with mifepristone (RU 486). J. Clin. Endocrinol. Metab., 73, 187191.[Abstract]
Lamberts, S.W., Tanghe, H.L., Avezaat, C.J., Braakman, R., Wijngaarde, R., Koper, J.W. and de Jong, H. (1992) Mifepristone (RU 486) treatment of meningiomas. J. Neurol. Neurosurg. Psychiat., 55, 486490.[Abstract]
Larner, J.M., Reel, J.R. and Blye, R.P. (2000) Circulating concentrations of the antiprogestins CDB-2914 and mifepristone in the female rhesus monkey following various routes of administration. Hum. Reprod., 15, 11001106.
Laue, L., Lotze, M.T., Chrousos, G.P., Barnes, K., Loriaux, D.L. and Fleisher, T.A. (1990) Effect of chronic treatment with the glucocorticoid antagonist RU 486 in man: toxicity, immunological, and hormonal aspects. J. Clin. Endocrinol. Metab., 71, 14741480.[Abstract]
Murphy, A., Kettel, L., Morales, A., Roberts, V. and Yen, S. (1993) Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J. Clin. Endocrinol. Metab., 76, 513517.[Abstract]
Newfield, R.S., Spitz, I.M., Isacson, C. and New, M.I. (2001) Long-term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia. Clin. Endocrinol. (Oxf.), 54, 399404.[CrossRef][ISI][Medline]
Nieman, L.K. and Loriaux, D.L. (1988) The use of anti-progesterones as a medical IUD. Baillières Clin. Obstet. Gynecol., 2, 609616.[ISI][Medline]
Nieman, L.K., Chrousos, G.P., Kellner, C., Spitz, I.M., Nisula, B.C., Cutler, G.B., Merriam, G.R., Bardin, C.W. and Loriaux, D.L. (1985) Successful treatment of Cushings syndrome with the glucocorticoid antagonist RU 486. J. Clin. Endocrinol. Metab., 61, 536540.[Abstract]
Odell, W.D., Rayford, P.L. and Ross, G.T. (1967) Simplified, partially automated method for radioimmunoassay of human thyroid-stimulating, growth, luteinizing, and follicle stimulating hormones. J. Lab. Clin. Med., 70, 973980.[ISI][Medline]
Perrault, D., Eisenhauer, E.A., Pritchard, K.I., Panasci, L., Norris, B., Vandenberg, T. and Fisher, B. (1996) Phase II study of the progesterone antagonist mifepristone in patients with untreated metastatic breast carcinoma: a National Cancer Institute of Canada Clinical Trials Group study. J. Clin. Oncol., 14, 27092712.[Abstract]
Pomara, N., Doraiswamy, P.M., Tun, H. and Ferris, S. (2002) Mifepristone (RU 486) for Alzheimers disease. Neurology, 58, 1436.
Rao, P.N., Acosta, C.K., Cessac, J.W., Bahr, M.L. and Kim, H.K. (1999) Synthesis of N-desmethyl derivatives of 17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione and mifepristone. 1: Substrates for the synthesis of radioligands. Steroids, 64, 205212. [CrossRef][ISI][Medline]
Reel, J.R., Hild-Petito, S. and Blye, R.P. (1998) Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple, or continuous doses to rats. Contraception, 58, 129136.[CrossRef][ISI][Medline]
Schaison, G., George, M., Lestrat, N., Reinberg, A. and Baulieu, E.E. (1985) Effects of the anti-progesterone RU486 during mid-luteal phase in normal women. J. Clin. Endocrinol. Metab., 61, 484489.[Abstract]
Shoupe, D., Mishell, D., Lahteenmaki, P., Heikinheimo, O., Birgerson, L., Madkour, H. and Spitz, I.M. (1987) Effects of the antiprogesterone RU 486 in normal women. Am. J. Obstet. Gynecol., 157, 14151420.[Medline]
Spitz, I.M., Croxatto, H.B., Lahteenmaki, P., Heikinheimo, O. and Bardin, C.W. (1994) Effect of mifepristone on inhibition of ovulation and induction of luteolysis. Hum. Reprod., 9 (Suppl. 1), 6976.[ISI][Medline]
Stratton, P., Hartog, B., Hajizadeh, N., Piquion, J., Sutherland, D., Merino, M., Lee, Y.J. and Nieman, L.K. (2000) A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women. Hum. Reprod., 15, 10921099.
Tarantal, A.F., Hendrickx, A.G., Matlin, S.A., Lasley, B.L., Gu, Q.Q., Thomas, C.A., Vince, P.M. and Van Look, P.F. (1996) Effects of two antiprogestins on early pregnancy in the long-tailed macaque (Macaca fascicularis). Contraception, 54, 107115.[CrossRef][ISI][Medline]
Teutsch, G. and Philibert, D. (1994) History and perspectives of antiprogestins from the chemists pont of view. Hum. Reprod., 9 (Suppl. 1), 1231.[ISI][Medline]
Ulmann, A. and Silvestre, L. (1994) RU486: the French experience. Hum. Reprod., 9 (Suppl. 1), 126130.[ISI][Medline]
Wagner, B.L., Pollio, G., Giangrande, P. et al. (1999) The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: implications for the development of dissociated antiprogestins. Endocrinology, 140, 14491458.
Webb, A.M., Russell, J. and Elstein, M. (1992) Comparison of Yuzpe regimen, danazol and Mifepristone (RU486) in oral postcoital contraception. Br. Med. J., 305, 927931.[ISI][Medline]
Wiedemann, K., Lauer, C.J., Hirschmann, M., Knaudt, K. and Holsboer, F. (1998) Sleependocrine effects of mifepristone and megestrol acetate in healthy men. Am. J. Physiol., 274, E139145.[ISI][Medline]
Yamaoka, K., Nakagawa, J. and Uno, T. (1978) Application of Akaikes information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J. Pharmacokinet. Biopharm., 2, 165175.
Submitted on October 21, 2002; resubmitted on April 11, 2003; accepted on May 9, 2003.