RESUMEN
GnRH antagonists are used to prevent premature LH surges in assisted reproduction. The pregnancy rates obtained in several studies have been similar to those obtained in the long protocol with gonadotrophin-releasing hormone (GnRH) agonists. However, lower oestrogen serum concentrations have been observed and fewer oocytes retrieved using GnRH antagonists. Thus, potential effects at extrapituitary GnRH receptors in the ovary and the endometrium have been claimed. The article reviews the currently available data from the literature as well as current investigations with respect to effects of cetrorelix on the ovary and the endometrium. No evidence was found to support the hypothesis of extrapituitary effects of GnRH antagonists such as cetrorelix at doses used in assisted reproduction.
Asunto(s)
Endometrio/metabolismo , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/metabolismo , Ovario/metabolismo , Técnicas Reproductivas Asistidas , Estrógenos/sangre , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/sangre , Células de la Granulosa/metabolismo , Humanos , Hormona Luteinizante/sangre , Embarazo , Resultado del Embarazo , Receptores LHRH/metabolismoRESUMEN
Cetrorelix was administered in differing daily dosages for controlled ovarian stimulation. The dosage levels were 3 mg (9 cycles), 1 mg (19 cycles), 0.5 mg (43 cycles), 0.25 mg (46 cycles) and 0.1 mg (7 cycles). In the 3 mg, 1 mg and 0.5 mg group the respective median plasma concentrations of cetrorelix on the day of oocyte pick-up (OPU) were 2.10 ng/ml, 1.42 ng/ml and 0.88 ng/ml and 1.03 ng/ml, 0.46 ng/ml and 0.49 ng/ml on the day of embryo transfer (ET). In the 0.25 mg and 0.1 mg groups plasma cetrorelix levels were below the limit of quantification. The cetrorelix concentrations in follicular fluid (FF) in the 0.25 mg group were detectable in only 14 out of 44 samples, while in the 0.1 mg group no detectable concentrations could be obtained. We also examined 80 cycles after single doses of 5 mg (7 cycles), 3 mg (42 cycles), and 2 mg (31 cycles) cetrorelix. On the day of OPU the respective median plasma concentrations of cetrorelix were 0.57 ng/ml, 0.62 ng/ml, and 0.56 ng/ml, and 0.61 ng/ml and 0.28 ng/ml on the day of ET in the 5 mg and 3 mg groups. In the 2 mg group, the plasma concentrations fell to below limits of quantification in 8/9 samples on the day of ET. In 26 out of 27 FF samples cetrorelix was detectable in the 3 mg single dose group (median level: 0.69 ng/ml).
Asunto(s)
Fertilización In Vitro , Líquido Folicular/química , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/análisis , Hormona Liberadora de Gonadotropina/sangre , Inducción de la Ovulación , Adulto , Gonadotropina Coriónica/administración & dosificación , Transferencia de Embrión , Femenino , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Oocitos , Recolección de Tejidos y ÓrganosRESUMEN
OBJECTIVE: To summarize data from completed phase II and III clinical trials on children born after controlled ovarian stimulation using the luteinizing hormone-releasing hormone antagonist cetrorelix. DESIGN: All children born after ovarian stimulation in patients treated for infertility who were in prospective studies until March 23, 1999. SETTING: Academic research center. PATIENT(S): Children born after IVF or IVF plus ICSI. INTERVENTION(S): Controlled ovarian stimulation with cetrorelix in a multiple-dose or single/dual-dose protocol. MAIN OUTCOME MEASURE(S): Outcome of pregnancy and, in deliveries, the date of birth, number and sex of children born, birth weight, body length, and abnormalities were recorded. At approximately 1 year of age and 2 years of age, body weight and length and abnormalities in physical and mental development were recorded. RESULT(S): Two hundred nine and 18 children were born after fresh and frozen embryo transfers, respectively. Of the pregnancies, 76.2% (179 of 234) resulted in live birth and ectopic pregnancy occurred in 3.4% (8 of 231); one heterotopic pregnancy and four induced abortions were recorded. The malformation rate among all live births, stillbirths, and aborted fetuses was 3.1%. CONCLUSION(S): Use of cetrorelix in controlled ovarian stimulation does not harm the subsequently born children.
Asunto(s)
Fármacos para la Fertilidad Femenina/efectos adversos , Fertilización In Vitro , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/efectos adversos , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/efectos adversos , Ovario/efectos de los fármacos , Adulto , Estudios de Cohortes , Anomalías Congénitas/epidemiología , Transferencia de Embrión , Europa (Continente)/epidemiología , Femenino , Muerte Fetal/epidemiología , Estudios de Seguimiento , Alemania/epidemiología , Salud , Humanos , Lactante , Recién Nacido , Embarazo , Complicaciones del Embarazo/epidemiología , GemelosRESUMEN
A prospective, randomized study was performed to compare the efficiency of hormonal stimulation for IVF (in vitro fertilization) in either the long luteal protocol, using the LHRH agonist Buserelin, or the multiple dose LHRH antagonist protocol, using the LHRH antagonist Cetrorelix. Here we present the data on the incidence of ovarian hyperstimulation syndromes (OHSS). 85 and 188 patients were recruited for the stimulation in the LHRH agonist and in the LHRH antagonist protocol, respectively. The groups were comparable regarding anamnestic data. The incidence of WHO degrees II and degrees III OHSS was significantly lower in the Cetrorelix than in the Buserelin group (1.1% vs. 6.5%, p=0.03). Additionally 3 patients in the Cetrorelix group (1.6%) and 5 patients in the Buserelin group (5.9%) did not receive hCG because of a threatening OHSS. The follicle maturation was more homogeneous in the Cetrorelix protocol, with less small follicles on the day of hCG administration but a similar number of oocyte cumulus complexes retrieved. The pregnancy rates per cycle were not significantly different in the Cetrorelix and Buserelin protocol (22% vs. 26%). The Cetrorelix multiple dose protocol is advantageous compared to the long protocol regarding the incidence of OHSS, a potentially life threatening complication of controlled ovarian stimulation.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/uso terapéutico , Antagonistas de Hormonas/uso terapéutico , Síndrome de Hiperestimulación Ovárica/prevención & control , Técnicas Reproductivas , Buserelina/uso terapéutico , Esquema de Medicación , Femenino , Fármacos para la Fertilidad Femenina/uso terapéutico , Hormona Liberadora de Gonadotropina/administración & dosificación , Antagonistas de Hormonas/administración & dosificación , Humanos , Incidencia , Estudios ProspectivosRESUMEN
This retrospective study was performed to examine the implantation and pregnancy rates of frozen-thawed pronuclear stage oocytes obtained with the use of a GnRH antagonist, Cetrorelix (Cetrotide((R)) ASTA-Medica, Frankfurt/M, Germany) used in a multidose protocol with hMG, and to compare these results with those obtained after a conventional long GnRH analogue protocol (Decapeptyl-Depot, Ferring, Kiel, Germany). The study population consisted of 31 infertile couples with frozen-thawed pronuclear stage oocytes after ICSI treatment using the GnRH antagonist Cetrorelix (Cetrorelix((R))) and 31 infertile couples with frozen-thawed pronuclear stage oocytes after ICSI treatment using the long GnRH analogue protocol. Patients underwent ICSI after down regulation with a GnRH agonist (Decapeptyl) and stimulation with hMG, or a GnRH antagonist (Cetrorelix) and hMG. The supernumerary pronuclear stage oocytes were cryopreserved and transferred in a later mildly stimulated cycle. The implantation and pregnancy rates for frozen-thawed pronuclear stage oocytes derived from the GnRH antagonist compared with the GnRH agonist were 3.26% versus 3.73% (P=1.0000) and 8.33% versus 10.25% (P=1.0000), respectively. To our knowledge we report here the first pregnancies obtained by the transfer of cryopreserved pronuclear stage embryos generated from ICSI using a GnRH antagonist in the collecting cycle. The use of Cetrorelix in a multiple dose protocol in combination with hMG does not demonstrate a negative effect on viability, implantation potential or pregnancy outcome as compared to 2PN conceptuses obtained from a long GnRH agonist-hMG protocol.
Asunto(s)
Criopreservación , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/administración & dosificación , Oocitos/fisiología , Inyecciones de Esperma Intracitoplasmáticas , Aborto Espontáneo , Implantación del Embrión , Transferencia de Embrión , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Infertilidad/terapia , Menotropinas/administración & dosificación , Embarazo , Resultado del Embarazo , Estudios Retrospectivos , Pamoato de Triptorelina/administración & dosificaciónRESUMEN
A total of 346 women with normal ovulatory function was stimulated with human menopausal gonadotrophins (HMG) to attain ovarian stimulation for IVF or intracytoplasmic sperm injection (ICSI). Stimulation with HMG started on cycle day 2 or 3. After 6 days of stimulation, Cetrorelix in its minimum effective multiple dose of 0. 25 mg/day, was administered daily until induction of ovulation. In total, 333 patients (96.2%) reached the day of HCG administration, and 324 (93.6%) underwent oocyte retrieval. A mean of 25.2 ampoules of HMG was applied for a mean of 10.4 days. Cetrorelix was administered for a mean time lapse of 5.7 days. The mean normal fertilization rate was 60% in the IVF group and 59% in the ICSI group. Seventy pregnancies were attained, reflecting an ongoing clinical pregnancy rate of 24% per transfer. The ongoing clinical implantation rate was 11.4%. Only three cases of raised luteinizing hormone (LH) (>/=10 IU/l) with increased progesterone secretion (>/=1 ng/ml) were observed after initiation of Cetrorelix administration, reflecting an incidence of premature luteinization of 0.9%. The abortion rate was 17%. The incidence of severe ovarian hyperstimulation syndrome (World Health Organization grade III) was as low as 0.6%.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Antagonistas de Hormonas/administración & dosificación , Menotropinas/uso terapéutico , Inducción de la Ovulación , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos/fisiología , Femenino , Fertilización In Vitro , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/efectos adversos , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/efectos adversos , Humanos , Hormona Luteinizante/sangre , Síndrome de Hiperestimulación Ovárica/inducido químicamente , Inducción de la Ovulación/efectos adversos , Embarazo , Índice de Embarazo , Estudios ProspectivosRESUMEN
In this prospective and randomized study, 188 patients received the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix, and 85 patients the LHRH agonist buserelin to prevent endogenous luteinizing hormone (LH) surges during ovarian stimulation in in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Ultimately, 181 patients (96.3%) in the cetrorelix group, and 77 (90.6%) in the buserelin group, reached the day of the human chorionic gonadotrophin (HCG) injection. The mean number of human menopausal gonadotrophin (HMG) ampoules administered and the mean number of stimulation days with HMG were significantly less in the cetrorelix group than in the buserelin group (P < 0.01). A rise in LH and progesterone concentrations was observed in three of the 188 patients (1.6%) who received cetrorelix. On the day of the HCG administration, more follicles of a small diameter (11-14 mm) were observed in the buserelin group than in the cetrorelix group (P = 0. 02) and the mean serum oestradiol concentration was significantly higher in patients who received buserelin than in those who received cetrorelix (P < 0.01). Similar results were observed in fertilization, cleavage and pregnancy rates in the two groups. In conclusion, the use of the LHRH antagonists might be considered more advantageous because of the short-term application needed to inhibit gonadotrophin secretion, so allowing a reduction in the treatment time in a clinically significant manner.
Asunto(s)
Buserelina/uso terapéutico , Fármacos para la Fertilidad Femenina/uso terapéutico , Hormona Liberadora de Gonadotropina/análogos & derivados , Antagonistas de Hormonas/uso terapéutico , Inducción de la Ovulación , Adulto , Buserelina/efectos adversos , Gonadotropina Coriónica/uso terapéutico , Transferencia de Embrión , Femenino , Fármacos para la Fertilidad Femenina/efectos adversos , Hormona Liberadora de Gonadotropina/efectos adversos , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/uso terapéutico , Antagonistas de Hormonas/efectos adversos , Humanos , Hormona Luteinizante/sangre , Oocitos/fisiología , Síndrome de Hiperestimulación Ovárica/inducido químicamente , Embarazo , Índice de Embarazo , Progesterona/sangre , Estudios Prospectivos , Resultado del TratamientoRESUMEN
The luteal phase hormonal profile and the clinical outcome of 69 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) after ovarian stimulation with human menopausal gonadotrophin (HMG) and the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix were analysed. Twenty-four patients received Cetrorelix 0.5 mg (group I) while in 45 patients Cetrorelix 0.25 mg was administered (group II). Human chorionic gonadotrophin (HCG) was used as luteal support. Nine clinical pregnancies were obtained in group I (37.5%) and 12 in group II (26. 6%). These results were not significantly different. Serum progesterone and oestradiol concentrations did not differ between the two groups either in pregnant or non-pregnant patients. An expected decrease of the same hormones was observed 8 days after the pre-ovulatory HCG injection in non-pregnant women. With regard to serum luteinizing hormone concentrations, a decrease was observed 2 days after the pre-ovulatory HCG injection and was maintained at almost undetectable levels throughout the entire luteal phase in both conception and non-conception cycles of group I and group II. This study demonstrates that different doses of GnRH antagonist do not have any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given.
Asunto(s)
Fertilización In Vitro/métodos , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Fase Luteínica , Menotropinas/uso terapéutico , Inducción de la Ovulación , Resultado del Embarazo , Aborto Espontáneo , Adulto , Transferencia de Embrión , Femenino , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/uso terapéutico , Antagonistas de Hormonas/administración & dosificación , Antagonistas de Hormonas/uso terapéutico , Humanos , Hormona Luteinizante/sangre , Menotropinas/administración & dosificación , Microinyecciones , Embarazo , Embarazo Múltiple , Embarazo Tubario , Estudios Retrospectivos , GemelosRESUMEN
OBJECTIVE: To analyze the luteal phase of six patients undergoing controlled ovarian hyperstimulation (COH) with hMG and a new GnRH antagonist, Cetrorelix, without receiving luteal phase supplementation. DESIGN: Phase II study involving the first six patients who did not receive luteal phase support. SETTING: Tertiary referral center. PATIENT(S): Six healthy women undergoing COH for assisted reproductive techniques. INTERVENTION(S): Oocyte retrieval was performed 36 hours after hCG administration, followed by embryo transfer 2 days later. No luteal phase supplementation was given. MAIN OUTCOME MEASURE(S): Serum E2, progesterone, LH, and FSH concentrations were measured. RESULT(S): The length of the luteal phase was < or =12 days in three of the six patients. One of the patients in whom the luteal phase was >12 days had a low serum progesterone concentration (2.9 ng/mL) on day 10. Serum LH concentrations decreased after the preovulatory hCG injection in all patients. However, a progressive increase in LH was observed after day 7, reaching normal values. CONCLUSION(S): Corpus luteum function seems to be impaired in cycles that are stimulated with hMG and the GnRH antagonist Cetrorelix.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Antagonistas de Hormonas/uso terapéutico , Fase Luteínica/efectos de los fármacos , Menotropinas/uso terapéutico , Receptores LHRH/antagonistas & inhibidores , Superovulación , Adulto , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Hormona Luteinizante/sangre , Progesterona/sangreRESUMEN
A depot preparation of the third-generation gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix (SB-75) was used for preoperative treatment in twenty premenopausal patients with symptomatic uterine fibroids who were to undergo surgery. In a prospective, open, randomized setting 60 mg of Cetrorelix pamoate salt was administered i.m. on cycle day 2. Patients were randomized for a second dose of 30 or 60 mg of Cetrorelix depot, which was administered according to the degree of oestradiol suppression (<50 pg/ml) on treatment day 21 or 28. Surgery was done after 6 or 8 weeks of treatment, depending on second dosage administration. Weekly transvaginal sonography (TVS) and magnetic resonance imaging (MRI) before and after treatment was performed, for fibroid volume assessment. Sixteen patients showed satisfactory suppression of gonadotrophins and sex steroid secretion, avoiding any initial flare-up effect. In these patients a mean shrinkage rate of largest fibroid volume of 33.5% at the end of treatment could be observed according to TVS, while the mean shrinkage rate obtained after 14 days of treatment was 31.3%. In good responders (shrinkage >20%) largest fibroid volume at day 14 was approximately 56.7% of basic assessment. Although MRI showed minor mean shrinkage rates of only 25.4% of the initial volume, these differences in comparison to TVS assessment were not statistically significant. The avoidance of any initial flare-up in gonadotrophin secretion may explain this extremely fast reduction in fibroid size. The advantages of GnRH antagonist treatment in this indication consist in the short treatment time with a fast restoration of the ovarian function. The rate of poor responders may be reduced by using an improved slow release preparation.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Antagonistas de Hormonas/administración & dosificación , Leiomioma/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Adulto , Química Farmacéutica , Femenino , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Leiomioma/patología , Leiomioma/fisiopatología , Persona de Mediana Edad , Resultado del Tratamiento , Neoplasias Uterinas/patología , Neoplasias Uterinas/fisiopatologíaRESUMEN
The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 +/- 69.2 ml (range 89-1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 +/- 77.1 to a mean of 230.8 +/- 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall results support the use of Cetrorelix for the management of uterine leiomyomas.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/uso terapéutico , Leiomioma/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Adulto , Femenino , Fase Folicular , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Histerectomía , Leiomioma/diagnóstico por imagen , Leiomioma/cirugía , Fase Luteínica , Persona de Mediana Edad , Embarazo , Ultrasonografía , Hemorragia Uterina , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Uterinas/cirugía , Útero/diagnóstico por imagenRESUMEN
OBJECTIVE: To assess the minimal effective dose of a GnRH antagonist (Cetrorelix; Asta Medical; Frankfurt, Germany) to prevent premature LH surge in patients undergoing controlled ovarian hyperstimulation (COH) for assisted reproductive technologies. DESIGN: In 69 patients COH was carried out with the association of hMG, starting on day 2 of the menstrual cycle, and a GnRH antagonist (Cetrorelix) was administered from day 6 of the hMG treatment (day 7 of the menstrual cycle) every day up to and including the last day of the hMG injection. In 32 and 30 patients, 0.5 mg and 0.25 mg of Cetrorelix were administered, respectively. Seven patients received 0.1 mg of Cetrorelix. SETTING: Tertiary referral center. RESULT(S): No premature endogenous LH surge occurred in patients treated with 0.5 and 0.25 mg of Cetrorelix, and serum LH concentrations were maintained constantly low during the entire follicular phase in both groups. Follicle-stimulating hormone, LH, E2, and P expressed as area under the curve were similar in both groups. A premature LH surge (18 mIU/mL; conversion factor to SI unit, 1.00) with a concomitant P rise (1.7 micrograms/L; conversion factor to SI unit, 3.180) occurred in one of the seven patients treated with 0.1 mg Cetrorelix; therefore, treatment with this dose was discontinued. CONCLUSION(S): The minimal effective dose of Cetrorelix able to prevent premature LH surge in COH cycles is 0.25 mg administered daily.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/administración & dosificación , Inducción de la Ovulación/métodos , Adulto , Gonadotropina Coriónica/administración & dosificación , Gonadotropina Coriónica/uso terapéutico , Estradiol/sangre , Femenino , Fertilización In Vitro/métodos , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/uso terapéutico , Antagonistas de Hormonas/uso terapéutico , Humanos , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Microinyecciones , Progesterona/sangreRESUMEN
A third generation gonadotrophin-releasing hormone antagonist (Cetrorelix) was used during ovarian stimulation in 32 patients undergoing assisted reproduction, in order to prevent the premature luteinizing hormone (LH) surge. In all patients, ovarian stimulation was carried out with two or three ampoules of human menopausal gonadotrophin (HMG), starting on day 2 of the menstrual cycle. In addition, 0.5 mg of Cetrorelix was administered daily from day 6 of HMG treatment until the day of ovulation induction by human chorionic gonadotrophin (HCG). A significant drop in plasma LH concentration was observed within a few hours of the first administration of Cetrorelix (P < 0.005). Moreover, no LH surge was detected at any point in the treatment period in any of the 32 patients. A mean oestradiol concentration of 2111 +/- 935 ng/l was observed on the day of the HCG administration, indicating normal folliculogenesis. Like LH, progesterone concentration also dropped within a few hours of the first administration of Cetrorelix (P < 0.005). A 0.5 mg daily dose of Cetrorelix prevented a premature LH surge in all the 32 patients treated.
Asunto(s)
Fase Folicular/sangre , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Antagonistas de Hormonas/uso terapéutico , Hormonas/sangre , Menotropinas/uso terapéutico , Ciclo Menstrual/efectos de los fármacos , Adulto , Citoplasma , Femenino , Fertilización In Vitro , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Masculino , Microinyecciones , Oocitos , Espermatozoides , Resultado del TratamientoRESUMEN
In the present study, subtle serum progesterone rise (>= 1.1 ng/ml) during the late follicular phase is reported, for the first time to our knowledge, in patients using a potent gonadotrophin-releasing hormone (GnRH) antagonist, Cetrorelix, in combination with human menopausal gonadotrophin (HMG) for ovarian stimulation prior to intracytoplasmic sperm injection (ICSI). In five out of 24 patients (20%) serum progesterone levels were >/= 1.1 ng/ml. The cycle characteristics of the patients were similar in both groups. No premature endogenous luteinizing hormone (LH) surge occurred and the serum LH concentrations were constantly low during the follicular phase. The 17-beta oestradiol and follicle stimulating hormone (FSH) exposure were higher in cycles with premature luteinization. The greater oestradiol and FSH exposure confirm that one of the possible factors inducing subtle serum progesterone rise is the increased oestradiol and FSH-induced LH receptivity in granulosa cells.
Asunto(s)
Fertilización In Vitro/métodos , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Progesterona/sangre , Adulto , Citoplasma , Femenino , Fase Folicular/sangre , Hormona Liberadora de Gonadotropina/efectos adversos , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Masculino , Microinyecciones , Inducción de la Ovulación , EspermatozoidesRESUMEN
The tolerability and pharmacokinetics of azelastine hydrochloride (CAS 73907-93-0, A-05610) after single and multiple dosing (4.4 mg as tablet, tau = 12 h) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). The medication was administered as tablets in the morning of days 1 and 11, and b.i.d. on days 4 to 10 in a randomized, open-labelled, uncontrolled study. Tolerance proved to be very good. Reported number of adverse events was independent from height of plasma levels measured, which showed pronounced inter- and intraindividual variation. When comparing pharmacokinetic parameters from plasma levels (determined with a radioimmunoassay (RIA)) of the elderly with those of young volunteers (26 +/- 5 years), there is a difference in half lives (t1/2 elderly vs young: single dose: 38.5 +/- 15.3 h vs 25.0 +/- 5.2 h; multiple dose: 35.5 +/- 16.3 h vs 55.4 +/- 24.9 h), and also after a single dose AUC and after multiple dosing AUCss tau, tssmax, Cssmax, Cssmin (pre dose levels), and the ratios of accumulation Rmax and Rmin (calculated from Cssmax/Cmax and Cssmin/Cmin) are approximately twice as high in elderly as those in young volunteers. The RIA co-detects besides azelastine the pharmacodynamically active metabolite N-demethyl-azelastine and thus, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds, i.e. the "active principle". N-Demethylated metabolites are known to have longer half-lives usually than their parent compounds and thus, accumulate in a higher degree during multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ftalazinas/efectos adversos , Ftalazinas/farmacocinética , Adulto , Anciano , Envejecimiento/metabolismo , Método Doble Ciego , Femenino , Semivida , Humanos , MasculinoRESUMEN
In a double-blind, randomized, 4-period crossover study, single oral doses of azelastine hydrochloride tablets (A-05610, Allergodil, Radethazin, Azeptin, CAS 79307-93-0) were ingested by 12 healthy volunteers (6 males, 6 females, mean age 25.2 +/- 3.5 years). Dose linearity was demonstrated for 2.2, 4.4, 8.8 and 17.6 mg of azelastine hydrochloride. The values of AUC0-infinity and Cmax increased linear to the dose (means of AUC0-infinity: 47.3, 93.7, 208.0 and 405.90 ng-eq h/ml; means of Cmax: 1.5, 3.3, 6.0 and 12.5 ng-eq/ml), whereas tmax and the terminal half-life of elimination (t1/2 beta) were obviously not influenced by the dose. Mean values over all doses and subjects amounted to 4.6 h (tmax) and 25.5 h (t1/2 beta). Plasma levels showed relatively high inter- and somewhat less intraindividual variations. This is most likely due to a varying degree of enterohepatic circulation resulting from alimentary factors. As for the co-detection of azelastine and the pharmacodynamically active metabolite N-desmethyl-azelastine by the radio-immuno-assay (RIA) used, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds and thus the active principle of the drug. Independently of the dosages administered the overall tolerance proved to be very good. According to this trial the therapeutic range is wide enough to recommend 4.4 mg b.i.d. or single doses of 8.8 mg of azelastine hydrochloride per day for therapy in adult patients.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/efectos adversos , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Ftalazinas/efectos adversos , Ftalazinas/farmacocinética , Adulto , Método Doble Ciego , Femenino , Semivida , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Humanos , Masculino , Ftalazinas/administración & dosificación , Radioinmunoensayo , Caracteres SexualesRESUMEN
METHOD: To answer the question as to whether the analgesic flupirtine is suitable for long-term treatment of chronic pain, its side effects and efficacy were investigated over a 12-month treatment period. A total of 191 patients with chronic pain of degenerative and/or inflammatory musculoskeletal diseases were admitted to the open, uncontrolled multicenter study. This was followed by a single-blind placebo follow-up period of two weeks aimed at detecting withdrawal phenomena as a sign of a possible addictive potential of flupirtine. RESULTS: On the basis of patient and investigator documentation, laboratory studies and clinical examinations, flupirtine was found to be both well tolerated and effective. No signs of tolerance, addiction or relevant interactions were observed. The side effect profile differed from that of the opioids or prostaglandin synthesis inhibitors (NSAIDs).
Asunto(s)
Aminopiridinas/uso terapéutico , Analgésicos/uso terapéutico , Enfermedades Musculoesqueléticas/tratamiento farmacológico , Dolor/tratamiento farmacológico , Adulto , Anciano , Aminopiridinas/efectos adversos , Analgésicos/efectos adversos , Enfermedad Crónica , Femenino , Humanos , Cuidados a Largo Plazo , Masculino , Persona de Mediana Edad , Dimensión del DolorRESUMEN
A single oral dose of flupirtine maleate, a novel analgesic agent, did not antagonize significantly the diuretic action of frusemide when compared with indomethacin and placebo in normal human volunteers.
Asunto(s)
Aminopiridinas/farmacología , Analgésicos/farmacología , Diuresis/efectos de los fármacos , Furosemida/antagonistas & inhibidores , Indometacina/farmacología , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Distribución AleatoriaRESUMEN
Flupirtine maleate (referred to throughout this paper as flupirtine) capsules 100 mg and suppositories 150 mg were found to be safe and efficacious in several randomized, controlled, double-blind parallel group clinical trials. 586 patients (40 children) suffering from post-operative pain were treated. Flupirtine was significantly more effective than placebo and as well tolerated. It was as effective and acceptable as pentazocine and dihydrocodeine for the treatment of post-operative pain, but offered advantages in terms of fewer central nervous system side effects. It was at least as effective as the non-narcotics metamizole, paracetamol and naproxen.