RESUMEN
OBJECTIVE: To compare bleeding control, efficacy and safety of two dose-ranging continuous combined hormone replacement therapy (HRT) regimens with those of a conventional continuous combined HRT. METHODS: An open, 2-year, multicenter study was conducted in 393 postmenopausal women recruited from 16 study sites. The women were randomized to three continuous combined HRT regimens. One group (n = 131) started with 1 mg of estradiol valerate (E2V) plus 2.5 mg of medroxyprogesterone acetate (MPA), the second group (n = 130) received 1 mg E2V + 5 mg MPA and the third (n = 132) 2 mg estradiol (E2) and 1 mg norethisterone acetate (NETA). In the two E2V/MPA groups the initial E2V dose of 1 mg was increased to 2 mg after six cycles (one cycle = 28 days) to evaluate the effect of dose increase on bleeding control. RESULTS: The E2V/MPA regimens with a lower estrogen dose induced less bleeding and other adverse effects during the first six cycles than did the E2/NETA regimen. Bleeding disturbances and breast tenderness resulted in significantly more discontinuations in the E2/NETA group. After the estrogen dose increase in the E2V/MPA regimens, all groups showed comparable bleeding patterns and adverse effect profiles. The lower E2V dose was as effective as standard-dose E2 in relieving climacteric symptoms. All regimens provided excellent endometrial safety. No hyperplasias were reported. CONCLUSIONS: Continuous combined HRT should be started, and continued, with the lowest effective doses. An increase of the estrogen dose is recommended only if the initial dose is not sufficient for symptom control.
Asunto(s)
Anticonceptivos Femeninos/administración & dosificación , Estradiol/análogos & derivados , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno/métodos , Acetato de Medroxiprogesterona/administración & dosificación , Noretindrona/análogos & derivados , Noretindrona/administración & dosificación , Hemorragia Uterina/prevención & control , Anciano , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Femenino , Sofocos/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Acetato de NoretindronaRESUMEN
OBJECTIVES: We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E(2)V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E(2)) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. METHODS: 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E(2)V+2.5 mg MPA; 1 mg E(2)V+5 mg MPA; or 2 mg of E(2)+1 mg NETA. After the first 6 months, the E(2)V dose was increased to 2 mg in both E(2)V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. RESULTS: Significantly fewer bleeding days were experienced in the first 3 months by women taking E(2)V/MPA compared with women taking E(2)/NETA. When the dose of E(2)V was increased in the E(2)V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E(2)/NETA group compared with either of the E(2)V/MPA groups. The overall continuation rates ranged from 70 to 86%. CONCLUSIONS: These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E(2)V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.
Asunto(s)
Estradiol/análogos & derivados , Estradiol/administración & dosificación , Terapia de Reemplazo de Hormonas , Sofocos/prevención & control , Acetato de Medroxiprogesterona/administración & dosificación , Noretindrona/análogos & derivados , Noretindrona/administración & dosificación , Hemorragia Uterina/prevención & control , Anciano , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Endometrio/patología , Femenino , Francia , Alemania , Humanos , Persona de Mediana Edad , Acetato de Noretindrona , Cooperación del Paciente , Encuestas y Cuestionarios , Resultado del Tratamiento , Triglicéridos/sangreRESUMEN
OBJECTIVE: We sought to determine the optimum estradiol valerate-medroxyprogesterone acetate regimens for efficacy and safety. STUDY DESIGN: We performed a 24-month, randomized, double-blind phase II study. Four hundred nineteen women who were postmenopausal for at least 3 years were placed in six parallel treatment groups and received 1 or 2 mg estradiol valerate with either 2.5 or 5 mg medroxyprogesterone acetate. In two groups the dose of estradiol valerate was increased from 1 to 2 mg estradiol valerate after 6 months. RESULTS: A marked improvement of climacteric symptoms was observed, and most women had no bleeding even during the first 3 months of treatment. The best bleeding pattern was achieved with 1 mg estradiol valerate and 2.5 or 5 mg medroxyprogesterone acetate, and in most groups the bleeding pattern improved over time. No cases of hyperplasia were observed. CONCLUSION: All regimens alleviated climacteric symptoms and provided excellent bleeding control, even during the early weeks of treatment. A choice of various dose combinations offers flexibility of dosing, thus enabling therapy to be tailored to the needs of individual women.
Asunto(s)
Terapia de Reemplazo de Hormonas , Posmenopausia/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Climaterio/efectos de los fármacos , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Endometrio/efectos de los fármacos , Estradiol/análogos & derivados , Estradiol/uso terapéutico , Femenino , Hemorragia/prevención & control , Humanos , Lípidos/sangre , Acetato de Medroxiprogesterona/uso terapéutico , Persona de Mediana Edad , Posmenopausia/sangre , Posmenopausia/fisiología , Congéneres de la Progesterona/uso terapéuticoRESUMEN
We studied the effect of four continuous combined estradiol valerate (E2V) and medroxyprogesterone acetate (MPA) dose combinations in six treatment groups (n = 70 per group) receiving regimens containing 1 mg or 2 mg E2V combined to 2.5 mg or 5 mg MPA, on bone mineral density (BMD) and endometrium in 419 healthy postmenopausal women over 4 treatment years. In two groups the 1 mg dose of E2V was increased to 2 mg after the first 6 months, while the MPA doses remained constant (2.5 mg or 5 mg). The remaining four groups received 1 E2V + 2.5 mg MPA, 1 mg E2V + 5 mg MPA, 2 mg E2V + 2.5 mg MPA, or 2 mg E2V + 5 mg MPA throughout the study. BMD at the spine and hip was measured by dual-energy X-ray absorptiometry and endometrial biopsy samples were taken at 6, 12, 24, 36 and 48 month follow-ups. Combinations containing the low dose of 1 mg of E2V (with 2.5 mg or 5 mg MPA) resulted in a mean BMD increase of 6.2% at the spine and 2.9% at the femoral neck after 4 years of treatment. With 2 mg E2V the corresponding increases were 7.4% and 2.9%, respectively. The largest increases in BMD were seen in women for whom the E2V dose was doubled after the initial 6 months of treatment: 8.9% at the spine and 4.2% in the femoral neck. Both MPA doses (2.5 mg and 5 mg) effectively prevented estrogen-induced stimulation of the endometrium. No endometrial hyperplasia was observed in any of the treatment groups. Lower-dose combinations of continuous combined estrogen-progestin regimens are effective in increasing and maintaining BMD and provide a good endometrial safety profile for the long-term prevention of osteoporosis in postmenopausal women.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Endometrio/efectos de los fármacos , Congéneres del Estradiol/administración & dosificación , Estradiol/administración & dosificación , Acetato de Medroxiprogesterona/administración & dosificación , Osteoporosis Posmenopáusica/prevención & control , Congéneres de la Progesterona/administración & dosificación , Anciano , Análisis de Varianza , Método Doble Ciego , Combinación de Medicamentos , Terapia de Reemplazo de Estrógeno/métodos , Femenino , Humanos , Persona de Mediana Edad , Método Simple Ciego , Resultado del TratamientoRESUMEN
OBJECTIVE: To find out the effect of carmustine (bischloroethyl-nitrosourea) combined with a biodegradable polymer in the treatment of malignant (Grades III and IV) gliomas, applied locally, at the time of the primary operation. METHODS: Prospective, randomized double-blind study of an active treatment group versus a placebo group. Conducted at the Departments of Neurosurgery of the University Hospitals of Helsinki, Tampere, and Turku in Finland and Trondheim in Norway. The study consisted of 32 patients (16 in each treatment group) enrolled between March 23, 1992, and March 19, 1993. The study was planned to include 100 patients but had to be terminated prematurely, because the drug that was being used had become unobtainable. The main outcome measures included the survival times of patients after the operations and the application of an active drug or placebo. RESULTS: The median time from surgery to death was 58.1 weeks for the active treatment group versus 39.9 weeks for the placebo group (P = 0.012). For 27 patients with Grade IV tumors, the corresponding times were 39.9 weeks for the placebo group and 53.3 weeks for the active treatment group (P = 0.008). At the end of the study, six patients were still alive, five of whom belonged to the active treatment group. CONCLUSION: Carmustine applied locally in a biodegradable polymer at the time of primary operation, seems to have a favorable effect on the life span of patients with high-grade gliomas.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Carmustina/administración & dosificación , Glioma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/cirugía , Carmustina/efectos adversos , Quimioterapia Adyuvante , Terapia Combinada , Método Doble Ciego , Portadores de Fármacos , Implantes de Medicamentos , Femenino , Estudios de Seguimiento , Glioma/mortalidad , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Polímeros , Estudios Prospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
1. In two separate studies, each with 12 healthy male volunteers, the pharmacokinetic and dynamic properties of a transdermal delivery system for bopindolol were evaluated. 2. In study I it was shown that bopindolol absorption from a 14 mg patch occurred over the whole 7-day application period. No signs of a significant skin depot were found. 3. In study II, a linear pharmacokinetic behaviour but a non-linear kinetic/dynamic relationship was established for the patches over a dose range from 7 to 21 mg. Comparable peak effects of reduction in exercise-induced tachycardia were observed after different patch doses and an i.v. injection. However, the effect was significantly prolonged with the patches compared with the injection and was maintained over 7 days. 4. The patches showed a good local and systemic tolerability in both studies over a dosing interval of up to 7 days.