RESUMEN
BACKGROUND: Patients with psychotic depression exhibit elevated cortisol levels. Competitively antagonizing cortisol at the glucocorticoid receptor with mifepristone demonstrated therapeutic benefit in early studies of patients with psychotic depression. We present a combined analysis of all controlled phase 2 and 3 studies to report antipsychotic differences between treatment with mifepristone or placebo and to evaluate the relative contributions to response of attaining an a priori-defined, high mifepristone plasma level and markers of glucocorticoid receptor antagonism (increases in adrenocorticotropin hormone and cortisol) with treatment. METHODS: Data from five similarly designed double-blind phase 2 or 3 studies evaluating the efficacy and safety of 7-day treatment with mifepristone for the psychotic symptoms of psychotic depression were pooled for analysis (mifepristone n = 833; placebo n = 627). Clinical assessments were performed at baseline and on days 7, 14, 28, 42, and 56. Mifepristone, adrenocorticotropin hormone, and cortisol samples were collected at baseline and day 7. RESULTS: Combined results demonstrated meaningful efficacy (p < .004) for mifepristone in reducing psychotic symptoms with wide safety margins. Patients in the a priori-defined, high mifepristone plasma level group (≥1637 ng/mL) demonstrated a more significant treatment effect over placebo (p = .0004). A number needed to treat of 7 and 48 was observed in the high and low mifepristone plasma level groups, respectively. Adverse events were similar in mifepristone- and placebo-treated patients. CONCLUSIONS: A high mifepristone plasma level carried the strongest association with response, followed by changes in adrenocorticotropin hormone and cortisol. Therapeutic plasma levels of mifepristone were most likely to be achieved with the 1200 mg/day dose.
Asunto(s)
Antidepresivos/sangre , Antidepresivos/uso terapéutico , Depresión/sangre , Depresión/tratamiento farmacológico , Mifepristona/sangre , Mifepristona/uso terapéutico , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Psychotic depression has no Food and Drug Administration-approved treatment. Patients demonstrate significant dysregulation of the hypothalamic-pituitary-adrenal axis providing a biologically targeted treatment opportunity. The purpose of this study was to explore the clinical and biological effects of short-duration (7-day) glucocorticoid receptor antagonism with mifepristone and the role of mifepristone plasma levels in patients with psychotic depression. METHODS: This double-blind, randomized study took place at 34 US clinical research centers and included patients with a diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder, severe, with psychotic features. Patients underwent daily, observed, in-clinic administration of oral study drug (mifepristone 1200 mg or placebo) for days 1 to 7 of the 56-day trial, followed by treatment with a single Food and Drug Administration-approved antidepressant on days 8 to 56. The following scales were administered on days 0, 7, 14, 28, 42, and 56: Brief Psychiatric Rating Scale (BPRS), BPRS Positive Symptom Subscale, Hamilton Rating Scale for Depression, and Columbia-Suicide Severity Rating Scale. The primary end point was a categorical analysis evaluating the proportion of patients with 50% or greater reduction from baseline in BPRS Positive Symptom Subscale score on both days 7 and 56, demonstrating early and durable response. Cortisol and adrenocorticotropic hormone were measured on days 0, 7, 28, and 56. Mifepristone plasma levels were assessed on days 0 and 7. RESULTS: An interim analysis indicated that the primary efficacy end point was unlikely to be met, and the study was stopped early with 292 of the planned 450 patients enrolled. Although the primary end point was not met, in a secondary prespecified analysis, patients who attained a mifepristone plasma level of 1637 ng/mL or greater (defined a priori and termed the high plasma level; 66.7% of patients) demonstrated statistically significant reductions in psychotic symptoms compared with patients who received placebo starting on day 28. This group also showed nonsignificant, numeric superiority on Hamilton Rating Scale for Depression improvement. No significant improvements were observed in the low-mifepristone group (<1637 ng/mL) versus the placebo group. There were no significant differences in Columbia-Suicide Severity Rating Scale suicidality ratings between groups. CONCLUSIONS: Mifepristone 1200 mg daily for 7 days was safe and well tolerated, allowing most treated patients to achieve the a priori defined therapeutic plasma level of 1637 ng/mL, the mifepristone level associated with biological effect and clinical benefit.
Asunto(s)
Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/tratamiento farmacológico , Mifepristona/sangre , Mifepristona/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Hormona Adrenocorticotrópica/sangre , Adulto , Antidepresivos/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Persona de Mediana Edad , Mifepristona/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
Mifepristone (RU486) is a chemical abortifacient used by hundreds of millions of women world-wide. It has recently been used in clinical trials for psychotic depression and cancer chemotherapy. Metapristone is the most predominant biological active metabolite of mifepristone, and being developed as a novel cancer metastasis chemopreventive agent based on its unique pharmacological properties. In this study, a novel rapid and sensitive method using UPLC/MS/MS was developed and validated for quantitative analysis of metapristone in plasma, which used less plasma volume and was demonstrated to be more simple and low-cost than the published methods. Metapristone in plasma was recovered by liquid-liquid extraction using 1 mL of ethyl acetate and chromatographic separation was carried on a C18 column at 35 °C, with a gradient mobile phase consisting of methanol and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The mass spectrometric detection was carried out using a triple-quadrupole system via positive electrospray ionization. Multiple reaction monitoring was used for quantitation of m/z transitions from 416.3 to 119.9 for metapristone and from 313.1 to 109 for levonorgestrel (internal standard). Good linearity (r²> 0.9926) was achieved over a concentration range from 7.1 to 2840 ng/mL with a lower limit of quantification of 7.1 ng/mL for metapristone. The intra- and inter-day variations of the assay were 2.4-10.0% relative standard deviation with an accuracy of -5.6 to 8.6% relative error. This newly developed method was successfully applied to a pharmacokinetic study that revealed, for the first time, that there was a significant difference in pharmacokinetic profile between genders.
Asunto(s)
Anticarcinógenos/sangre , Cromatografía Líquida de Alta Presión/métodos , Mifepristona/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Animales , Femenino , Límite de Detección , Masculino , Mifepristona/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Mifepristone is approved to control hyperglycemia in adults with endogenous Cushing's syndrome and is described as a mildly QTc prolonging drug, based on a TQT study. The aim of the present study was to assess the effect of mifepristone on the QTc interval at plasma mifepristone concentrations exceeding those observed in the TQT study. METHODS: Twenty healthy, male volunteers were given three doses of 1200 mg mifepristone every 12 h with a high-fat meal in a randomized, placebo-controlled 2-period crossover study. Holter ECG recordings were made on Day 1 and 2. RESULTS: Eighteen subjects completed the study. Mean peak plasma mifepristone concentrations were 4.01 µg/mL (CV: 31%) on the fi rst dose and 5.77 µg/mL (CV: 29%) on the third dose. Mifepristone did not have a meaningful QTc effect. The placebo-corrected, change-from- -baseline QTcF (ΔΔQTcF) was between -1.6 and 0.7 ms on the fi rst dose (upper bound of 90% CI 3.8 ms) and the largest ΔΔQTcF on the third dose was 4.9 ms (upper bound of 90% CI: 8.4 ms). Concentration effect modeling showed a slightly negative slope of -0.01 ms/ng/mL. CONCLUSIONS: Mifepristone did not cause a clinically meaningful QTc prolongation in healthy volunteers at plasma concent rations of mifepristone and its main metabolites that clearly exceeded those seen in a previous TQT study.
Asunto(s)
Hipoglucemiantes/farmacocinética , Mifepristona/farmacocinética , Administración Oral , Adulto , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Electrocardiografía , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/sangre , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Mifepristona/administración & dosificación , Mifepristona/efectos adversos , Mifepristona/sangre , Medición de Riesgo , Factores de RiesgoRESUMEN
A sensitive liquid chromatography-mass spectrometric method was validated for the quantification of RU38486 (mifepristone) in human and murine plasma. The analyte and internal standard (alfaxolone) were extracted by liquid-liquid extraction with diethyl ether, resolved on a C18 column using gradient elution with methanol and ammonium acetate and detected after positive electrospray ionization (m/z 430-->372; m/z 333-->297, respectively). Quantification was linear over the range 0.5-500ng (r(2)>0.997), precise and accurate (intra-assay RSD< or =7.2%, RME< or =8.2%; inter-assay RSD< or =15.7% RME< or =10.2%). The limit of quantification (LOQ) was 50pg injected on column, permitting reproducible analysis of RU38486 in small volumes of plasma.
Asunto(s)
Espectrometría de Masas/métodos , Mifepristona/sangre , Adulto , Animales , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Antagonistas de Hormonas/sangre , Antagonistas de Hormonas/química , Humanos , Masculino , Ratones , Mifepristona/química , Peso Molecular , Solventes , TemperaturaRESUMEN
A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine mifepristone and monodemethyl-mifepristone in human plasma using levonorgestrel as the internal standard (IS). After solid-phase extraction of the plasma samples, mifepristone, monodemethyl-mifepristone and the IS were subjected to LC-MS/MS analysis using electro-spray ionization (ESI) in the multiple reaction monitoring (MRM) mode. Chromatographic separation was performed on an XTERRA MS C(18) column (150 x 2.1 mm i.d., 5 microm). The method had a chromatographic run time of 4.5 min and linear calibration curves over the concentration ranges of 5-2000 ng/mL for mifepristone and monodemethyl-mifepristone. The recoveries of the method were found to be 94.5-103.7% for mifepristone and 70.7-77.3% for monodemethyl-mifepristone. The method had a lower limit of quantification (LLOQ) of 5.0 ng/mL and a lower limit of detection (LOD) of 1.0 ng/mL for both mifepristone and monodemethyl-mifepristone. The intra- and inter-batch precision was less than 15% for all quality control samples at concentrations of 10, 100 and 1000 ng/mL. These results indicate that the method was efficient with a short run time (4.5 min) and acceptable accuracy, precision and sensitivity. The validated LC-MS/MS method was successfully used in a pharmacokinetic study in healthy female volunteers after oral administration of 25 mg mifepristone tablet.
Asunto(s)
Cromatografía Liquida/métodos , Levonorgestrel/análisis , Mifepristona/sangre , Espectrometría de Masas en Tándem/métodos , Humanos , Levonorgestrel/normas , Mifepristona/análogos & derivados , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
A HPLC method with UV detection was developed and validated for the simultaneous determination of rivanol and mifepristone in human plasma. Norethisterone was used as the internal standard. Separation was performed by a C18 reversed-phase column maintained at 20 degrees C. The mobile phase was a mixture of methanol-acetonitrile-0.05% sodium dodecylsulfonate in a 0.05 M phosphate buffer with the pH adjusted to 3.0 (30:30:40, v/v/v) at a flow rate of 0.8 ml/min. Dual wavelength mode was used, with mifepristone monitored at UV 302 nm, while rivanol and norethisterone at 272 nm. A reliable biological sample pre-treatment procedure by means of solid-phase extraction was used, which allowed to obtain good extraction efficiency (>93%) for both of the analytes and the internal standard. The calibration curves were both linear with the correlation coefficient r equal to 0.9999. For rivanol, the assay gave CV% values for precision always lower than 7.8% and mean accuracy values higher than 95.3%. As to mifepristone, precision was always lower than 10.1% and mean accuracy values were higher than 93.8%. The limit of detection for the assay of rivanol and mifepristone was 1.1 and 3 ng/ml, respectively. The method is simple, sensitive and accurate, and allow for simultaneous determination of nanogram levels of rivanol and mifepristone in human plasma. It could be applied to assess the plasma level of rivanol and mifepristone in women undergoing polypharmacy with the two drugs.
Asunto(s)
Abortivos/sangre , Cromatografía Líquida de Alta Presión/métodos , Etacridina/sangre , Mifepristona/sangre , Espectrofotometría Ultravioleta/métodos , Humanos , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: The objective of this study was to develop a simple, sensitive, stable and validated HPLC method for the determination of mifepristone levels in human plasma. METHODS: Solid-phase extraction cartridges were used to extract plasma samples. Separation was carried out on a C(18) column maintained at 20 degrees C with acetonitrile-water (80:20, v/v) as mobile phase at a flow rate of 0.6 mL/min. Norethisterone was employed as the internal standard. Dual wavelength mode was used, with mifepristone monitored at UV 302 nm and norethisterone at 240 nm. RESULTS: The calibration curve was linear in the concentration range of 5-10000 ng/mL, with linear correlation coefficient r being 0.9999. The limit of detection for the assay was 3 ng/mL. The inter-day accuracy ranged from 92.4% to 98.4% and precision 3.6% to 11.4%. The intra-day accuracy ranged from 92.1% to 100.6% and precision 4.7% to 12.2%. The absolute recovery was 91.7-100.1%. Plasma samples were stable for at least 1 month if stored at -20 degrees C. This validated HPLC method was successfully applied to pharmacokinetic study of mifepristone in human plasma samples collected from volunteers after oral administration of 10 mg mifepristone. CONCLUSION: The simple, accurate and stable method allows the sensitive determination of mifepristone in human plasma at the nanogram level. It could be applied to assess the plasma level of mifepristone in women up to 5 days after oral administration of 10 mg mifepristone.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Anticonceptivos Sintéticos Orales/sangre , Mifepristona/sangre , Adulto , Femenino , Humanos , Noretindrona/sangreRESUMEN
Selecting the most reliable method to deliver exogenous steroids remains a problem for researchers, particularly when designing experiments on small birds. We used intraperitoneal (IP) osmotic pumps to deliver exogenous corticosterone (CORT) and RU486 in captive White-throated Sparrows. Males received implants containing either a low (LD) or moderate dose (MD) of CORT, RU486 (RU), or polyethylene glycol vehicle only (V). This method provided sustained elevations in baseline CORT in both LD and MD males compared to V males, with higher CORT levels induced in MD males. Slight increases in post-implant CORT resulted in V males, but not in RU males. We observed no significant change in the condition of V males in terms of body mass, furcular fat score or food intake rates, although locomotor activity declined slightly after implantation. Taken together, our results suggest that IP pumps had little impact on the overall health of the birds. CORT levels were maintained within natural ranges for this species, suggesting that our results are biologically relevant and useful for future endocrine studies with small birds.
Asunto(s)
Corticosterona/administración & dosificación , Corticosterona/farmacología , Bombas de Infusión Implantables , Gorriones , Animales , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Masculino , Mifepristona/administración & dosificación , Mifepristona/sangre , Factores de TiempoRESUMEN
An HPLC method was developed and validated for the determination of mifepristone in human plasma. C(18) solid-phase extraction cartridges were used to extract plasma samples. Separation was by C(18) column; mobile phase, methanol-acetonitrile-water (50:25:25, v/v/v); flow rate, 0.8 ml/min; UV detection at 302 nm. The calibration curve was linear in the concentration range of 10 ng/ml to 20 microg/ml (r=0.9991). Within- and between-day variability were acceptable. The limit of detection for the assay was 6 ng/ml. Plasma samples were stable for at least 7 days in the state of plasma or residue treated at -20 degrees C. The method was simple, sensitive and accurate, and allowed to determine ng mifepristone in human plasma. It could be applied to assess the plasma level of mifepristone in women receiving low oral doses of mifepristone.
Asunto(s)
Abortivos/sangre , Cromatografía Líquida de Alta Presión/métodos , Mifepristona/sangre , Calibración , Humanos , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría UltravioletaRESUMEN
Reliable correlations between the parameters of mifepriston pharmacokinetics describing the rate of drug elimination from the blood plasma and the levels of beta-human chorionic gonadotropin (beta-HCG) and progesterone reflecting the state of gestation in females have been established fore the first time. According to these relationships, the half elimination time, the mean retention time, and the plasma clearance of mifepriston can be considered as predictors of the clinical efficacy of this drug for the early pregnancy interruption.
Asunto(s)
Abortivos Esteroideos/farmacocinética , Aborto Inducido/métodos , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Mifepristona/farmacocinética , Embarazo/sangre , Abortivos Esteroideos/sangre , Adulto , Femenino , Humanos , Mifepristona/sangre , PlasmaRESUMEN
Glucocorticoid receptors (GRs) are present at a high density in the nucleus of the solitary tract (NTS), an area of the dorsal hindbrain (DHB) that is critical for blood pressure regulation. However, whether these receptors play any role in the regulation of blood pressure is unknown. We tested the hypothesis that glucocorticoids act in the DHB to increase arterial pressure using two experimental strategies. In one approach, we implanted pellets of corticosterone (Cort) or sham pellets onto the DHB over the NTS. Compared with rats with sham pellets, rats with DHB Cort pellets had an increased (P < 0.05) mean arterial pressure (111 +/- 2 vs. 104 +/- 1 mmHg) and heart rate (355 +/- 9 vs. 326 +/- 5 beats/min) after 4 days. In the second approach, we implanted subcutaneous Cort pellets to increase the systemic Cort concentration and then subsequently implanted pellets of the GR antagonist mifepristone (Mif; previously RU-38486) or sham pellets onto the DHB. Two days of DHB Mif treatment reduced (P < 0.05) mean arterial pressure in those rats with elevated plasma Cort levels (118 +/- 2 vs. 108 +/- 1 mmHg for sham vs. Mif DHB pellets). Cort and Mif pellets placed on the dura had no effects on arterial pressure or heart rate, ruling out systemic cardiovascular effects of the steroids. DHB Cort treatment had no effects on plasma Cort concentration or adrenal weight, indicating that the contents of the DHB Cort pellet did not diffuse into the systemic circulation or into the forebrain areas that regulate plasma Cort concentration in concentrations sufficient to produce physiological effects. Immunohistochemistry for the occupied GRs demonstrated that the Cort and Mif from the DHB pellets were delivered to the DHB with minimal diffusion to the ventral hindbrain or forebrain. We conclude that glucocorticoids act in the DHB to increase arterial pressure.
Asunto(s)
Presión Sanguínea/fisiología , Glucocorticoides/fisiología , Rombencéfalo/fisiología , Glándulas Suprarrenales/anatomía & histología , Animales , Presión Sanguínea/efectos de los fármacos , Ritmo Circadiano , Corticosterona/farmacocinética , Corticosterona/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Inmunohistoquímica , Masculino , Mifepristona/sangre , Mifepristona/farmacocinética , Mifepristona/farmacología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/metabolismo , Rombencéfalo/efectos de los fármacos , Rombencéfalo/metabolismo , Distribución TisularRESUMEN
The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25-30 h, and high micromolar serum concentrations following ingestion of doses of >/=100 mg of the drug. The serum transport protein-alpha 1-acid glycoprotein (AAG)-regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone-plus its metabolites-seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception-mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the >/=200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2-5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.
Asunto(s)
Anticonceptivos Sintéticos Poscoito/farmacocinética , Mifepristona/farmacocinética , Anticonceptivos Sintéticos Poscoito/sangre , Femenino , Humanos , Mifepristona/sangre , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
An HPLC method was developed to determine levels of mifepristone, in coyote (Canis latrans) serum where mifepristone will be used as an oral contragestive agent for nonlethal predator control. Serum samples were extracted using C(18) solid-phase extraction cartridges. A synthetic analog of mifepristone, RTI-3021-003, was used as the internal standard. Separation of the compounds was achieved by using a C(18) (150 x 4.6 mm) column. The mobile phase was 55% acetonitrile in water running at 1.0 ml/min with UV detection at 305 nm. The assay was linear in the range of 10 to 1000 ng/ml. Inter-day accuracies for 10, 200 and 1000 ng/ml were 95.9, 99.4 and 104.7%, respectively. Inter-day precisions measured by RSD were 19.8, 9.7 and 4.5%. Intra-day accuracies were 117, 106.9 and 99.4% for 10, 200 and 1000 ng/ml, respectively. Intra-day RSDs were 19.7, 3.7 and 9.3%, respectively. A simple, sensitive and validated HPLC analytical method was developed to quantitate mifepristone in canine serum.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Anticonceptivos Sintéticos Orales/sangre , Mifepristona/sangre , Animales , Carnívoros , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría UltravioletaRESUMEN
We studied plasma factors mediating suppression of NK activity (NKA) following surgery. Plasma from operated rats suppressed NKA of splenocytes, leukocytes, and purified natural killer (NK) cells, and charcoal stripping nullified suppression. The glucocorticoid antagonist mifepristone prevented suppression, whereas blockers of reactive oxygen metabolites, opioids, catecholamines, prostaglandin-E2, and histamine did not. NKA dropped as corticosterone levels peaked postoperatively, and administration of relevant doses of corticosterone suppressed NKA. Inhibition of glucocorticoid synthesis prevented plasma from suppressing NKA but merely attenuated NKA suppression in operated rats. Thus, postoperative concentrations of corticosterone can directly suppress NKA but additional factors probably act in vivo.
Asunto(s)
Citotoxicidad Inmunológica/fisiología , Glucocorticoides/fisiología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Laparotomía , Factores Supresores Inmunológicos/fisiología , Alprostadil/inmunología , Animales , Cimetidina/sangre , Cimetidina/farmacología , Corticosterona/administración & dosificación , Corticosterona/antagonistas & inhibidores , Corticosterona/sangre , Corticosterona/fisiología , Citotoxicidad Inmunológica/efectos de los fármacos , Dinoprostona/inmunología , Glucocorticoides/antagonistas & inhibidores , Glucocorticoides/biosíntesis , Glucocorticoides/sangre , Sueros Inmunes/sangre , Sueros Inmunes/farmacología , Inyecciones Subcutáneas , Cinética , Masculino , Mifepristona/sangre , Mifepristona/farmacología , Periodo Posoperatorio , Ratas , Ratas Endogámicas F344 , Factores Supresores Inmunológicos/antagonistas & inhibidores , Factores Supresores Inmunológicos/biosíntesis , Factores Supresores Inmunológicos/sangre , Células Tumorales CultivadasRESUMEN
We have developed a mammalian cell (COS-1) bioassay, which measures glucocorticoid bioactivity (GBA) directly from a small amount of human serum. The assay is based on the expression of human glucocorticoid receptor (GR) together with a coactivator protein and reporter plasmid containing GR response elements upstream of the luciferase gene. Ten microliters of human serum, in duplicate, are added directly to the cell culture medium, and GBA is derived from reporter gene activity. The assay differentiates between biopotencies of synthetic steroids, and importantly, mifepristone (RU486) is able to block glucocorticoid-induced response. The assay is sensitive (<15.6 nM cortisol in fetal calf serum) and precise, with the within- and between-assay coefficients of variation less than 8% and 10%, respectively. We measured serum GBA (bioassay) and cortisol (RIA) levels in 34 asthmatic children (age range, 5.7-14.2 yr) at baseline and after treatment with either inhaled budesonide (800 microg/d, n = 14), fluticasone propionate (500 microg/d, n = 14), or cromones (control group, n = 6). Pretreatment serum GBA and cortisol levels correlated strongly (r = 0.90, P < 0.0001, n = 34). Two months of treatment with inhaled budesonide resulted in excess GBA in circulation, which was not attributable to endogenous cortisol (P < 0.001). In the fluticasone propionate group, the presence of serum excess GBA was at the borderline of statistical significance (P < 0.08) after 2 months of inhalation therapy, and no excess GBA was detected in the cromone group. In conclusion, our bioassay enables measurement of mammalian cell response to bioactive glucocorticoids in circulation and provides a novel means to investigate patients receiving drugs acting through the GR.
Asunto(s)
Asma/sangre , Bioensayo/métodos , Glucocorticoides/sangre , Receptores de Glucocorticoides/metabolismo , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Células COS , Niño , Preescolar , Femenino , Genes Reporteros , Glucocorticoides/uso terapéutico , Antagonistas de Hormonas/sangre , Antagonistas de Hormonas/uso terapéutico , Humanos , Masculino , Mifepristona/sangre , Mifepristona/uso terapéutico , Receptores de Glucocorticoides/genética , TransfecciónAsunto(s)
Abortivos Esteroideos/administración & dosificación , Mifepristona/administración & dosificación , Abortivos no Esteroideos/administración & dosificación , Abortivos Esteroideos/sangre , Abortivos Esteroideos/farmacocinética , Administración Oral , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Mifepristona/sangre , Mifepristona/farmacocinética , Misoprostol/administración & dosificaciónRESUMEN
The overall aim of these studies was to investigate the oral and i.m. bioavailability of CDB-2914 in intact female rhesus monkeys, and to compare the serum concentrations of CDB-2914 with that of mifepristone following oral administration. In the first study, a 50 mg bolus of CDB-2914 per monkey was administered intravenously, orally or intramuscularly. The area under the serum concentration-time curve for 72 h (AUC(0-72)) following i.v. injection was 18 320 +/- 2718 ng/ml*h, and that for oral administration was 10 464 +/- 3248 ng/ml*h. Thus, the oral bioavailability of CDB-2914 equivalents was 56%. The AUC(0-168 h) following i.m. injection was 11 226 +/- 1130 ng/ml*h. Therefore, the i.m. bioavailability of CDB-2914 equivalents was 62%. In the second study, the serum concentrations of CDB-2914 and mifepristone equivalents were compared following an oral bolus dose in two different formulations. When administered at 5 mg/kg in aqueous suspending vehicle (ASV), the mean peak serum concentration (C(max)) of CDB-2914 equivalents (192 +/- 64 ng/ml) occurred at 5 +/- 1 h, whereas the C(max) of mifepristone equivalents (82 +/- 25 ng/ml) occurred at 3 +/- 1 h. Following administration in gelatin capsules (35 mg/monkey), the C(max) of CDB-2914 equivalents (129 +/- 24 ng/ml) occurred at 5 +/- 1 h, while the C(max) of mifepristone equivalents (31 +/- 8 ng/ml) occurred at 3 +/- 1 h. The serum concentration (AUC(0-120 h)) of CDB-2914 equivalents was 4.7- or 5. 3-fold greater than that of mifepristone equivalents when administered orally in ASV or gelatin capsules respectively. The serum protein binding characteristics of CDB-2914 were also studied. CDB-2914 bound to human alpha(1)-acid glycoprotein (AAG), but not with as high an affinity as mifepristone. In contrast, neither CDB-2914 nor mifepristone bound with high affinity to AAG, corticosteroid binding globulin or sex hormone binding globulin in monkey serum. Collectively, these results indicated that CDB-2914 was more efficiently absorbed than mifepristone following oral administration to female rhesus monkeys.
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Anticonceptivos Sintéticos Poscoito/administración & dosificación , Anticonceptivos Sintéticos Poscoito/sangre , Mifepristona/administración & dosificación , Mifepristona/sangre , Norpregnadienos/administración & dosificación , Norpregnadienos/sangre , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Anticonceptivos Sintéticos Poscoito/farmacocinética , Formas de Dosificación , Femenino , Humanos , Inyecciones Intramusculares , Inyecciones Intravenosas , Macaca mulatta , Mifepristona/farmacocinética , Norpregnadienos/farmacocinética , Globulina de Unión a Hormona Sexual/metabolismo , Transcortina/metabolismoRESUMEN
OBJECTIVE: To evaluate the efficacy of mifepristone in inducing labor in women with an unripe cervix, its effect on the cervix and on the status of the newborn. METHODS: In a prospective double-blind study, 36 post-term pregnant women with a Bishop score of 5 or less received either 400 mg mifepristone (n=24) or placebo (n=12). If, 48 hours after the treatment was started, labor had not begun or the Bishop score was 5 or less, the women were given 0.5 mg prostaglandin E2 intracervically, a treatment which was repeated 12 hours later, if necessary. RESULTS: During the first 48 hours following treatment, 19 (79.2%) of the women treated with mifepristone and two of the women (16.7%) treated with placebo went into labor. In addition, one and three women, respectively, had a ripe cervix at the end of the 48h period. The overall success rate was thus 83.3% for mifepristone and 41.7% for placebo (p=0.008; OR 14.8; 95% CI 2.1-107.6). The median time from the start of treatment to delivery was also shorter (mifepristone 36h23' and placebo 53h17'). Treatment with intracervical PGE2 was needed more often after the placebo. The duration of labor, however, tended to be shorter after placebo than after mifepristone in the women who delivered vaginally. The frequencies of instrumental delivery were similar in both treatment groups. The median Apgar score was slightly lower at 1 minute (p<0.05) following mifepristone treatment, but did not differ at 5 and 10 minutes. There was no difference between the two treatment groups in the umbilical pH at delivery. CONCLUSION: The results of the present study show that mifepristone is a simple and effective treatment for inducing labor in post-term women with an unripe cervix.
Asunto(s)
Antagonistas de Hormonas/uso terapéutico , Trabajo de Parto Inducido/métodos , Mifepristona/uso terapéutico , Adulto , Puntaje de Apgar , Maduración Cervical/efectos de los fármacos , Dinoprostona/uso terapéutico , Método Doble Ciego , Femenino , Sangre Fetal/química , Antagonistas de Hormonas/sangre , Humanos , Concentración de Iones de Hidrógeno , Recién Nacido , Mifepristona/sangre , Oportunidad Relativa , Embarazo , Resultado del Embarazo , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine the efficacy and safety of mifepristone for cervical ripening in post-term pregnancies. METHODS: Women with post-term pregnancies and Bishop scores less than 6 were assigned randomly to mifepristone (41 patients) or placebo (42 patients). Mifepristone was given orally in a dose of 400 mg. Efficacy was assessed by change in the Bishop score within 48 hours after treatment; a score of 6 or greater was considered a "strict" success. An "extended" success rate was defined, including all patients with scores of at least 6 or those who delivered within 48 hours of treatment. Antenatal safety was assessed by fetal heart rate testing before and throughout labor. Neonatal safety was assessed by Apgar score, arterial or venous pH of cord blood, and blood glucose level during the first 48 hours. Analysis used Student t test for continuous variables, Kruskal-Wallis test for ordinal data, and chi2 for categoric variables. RESULTS: Strict success was achieved in 10 of 18 mifepristone patients (55%) evaluated for Bishop score on day 2 versus 8 of 29 placebo patients (27.5%) (P=.004). Extended success was achieved in 33 mifepristone patients (80.5%) and 21 placebo patients (50.0%) (P=.004). There were no statistical differences with regard to number of cesareans or fetal and neonatal safety. CONCLUSION: Mifepristone proved effective for cervical ripening and reduced the time to delivery compared with placebo, but it did not improve the rate of cesarean. Our study did not include enough pregnancies to reach conclusions about fetal or neonatal safety.