RESUMEN
OBJECTIVE: To compare the efficacy of 0.5 and 1.0 mg estradiol in combination with different doses of drospirenone for the treatment of menopausal hot flushes. METHODS: This retrospective analysis included data from two prospective, randomized, double-blind, multicenter, placebo-controlled studies. Inclusion criteria were seven to eight moderate to severe hot flushes per day during the 1-week screening period. The focus was the rate of responders. A responder was defined as a subject that had at least a perceptible improvement of 19.1 hot flushes per week at 4 weeks and a substantial improvement of 40.3 hot flushes per week at 12 weeks compared to baseline. Secondary focus was the absolute change of moderate to severe hot flushes per week over 12 weeks. RESULTS: A total of 832 subjects were included. At baseline, the median weekly number of moderate to severe hot flushes was between 62 and 67. After 12 weeks of treatment, combinations of 0.5 and 1 mg estradiol achieved a median reduction of 54-55 and 57-64 moderate to severe hot flushes, respectively. In the 0.5-mg estradiol group, the responder rates for combinations with drospirenone 0.25 and 0.5 mg were 62.7% and 75.8%, respectively. In the 1-mg estradiol group, the responder rates for combinations with drospirenone 1, 2 and 3 mg were 86.7%, 100% and 89.7%, respectively. CONCLUSION: Effective relief from hot flushes can be reached within 12 weeks with estradiol doses of 0.5 and 1 mg in combination with different drospirenone doses.
Asunto(s)
Androstenos/administración & dosificación , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno/métodos , Estrógenos/administración & dosificación , Sofocos/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Androstenos/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Estradiol/uso terapéutico , Estrógenos/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Posmenopausia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: To investigate the long-term endometrial safety and bleeding pattern of the 0.25 mg drospirenone/0.5 mg 17ß-estradiol (DRSP/E2) dose combination compared with 0.5 mg norethisterone acetate (NETA)/1.0 mg E2, in postmenopausal women. METHODS: A total of 662 postmenopausal women aged between 40 and 65 years with an indication for hormone therapy verified by the investigator were randomized to participate in this 1-year, double-blind, active comparator-controlled study. The primary efficacy variable was the proportion of women with an endometrial biopsy assessment of 'hyperplasia or worse' at any time during or after 13 cycles of treatment. RESULTS: No evaluable women in the DRSP/E2 or NETA/E2 groups had an endometrial biopsy result of 'hyperplasia or worse'. The incidence of amenorrhea was higher in the DRSP/E2 group than the NETA/E2 group during months 1-3 (69.0% vs. 56.0%), with comparable amenorrhea rates of approximately 80% during months 10-12. Improvements in menopausal symptoms (exploratory efficacy variables) were similar in the two groups, while there were fewer women with treatment-related adverse events (18.4% vs. 25.6%) or adverse events leading to discontinuation of study drug (8.4% vs. 15.1%) in the DRSP/E2 group than the NETA/E2 group. There were no treatment-related thromboembolic or cardiovascular events in the DRSP/E2 group vs. two events in the NETA/E2 group. CONCLUSIONS: The low-dose, 0.25 mg DRSP/0.5 mg E2 dose combination met the criteria for endometrial safety and demonstrated a favorable risk/benefit profile in this 1-year, double-blind, randomized study of postmenopausal women.
Asunto(s)
Androstenos/administración & dosificación , Androstenos/efectos adversos , Endometrio/efectos de los fármacos , Estradiol/administración & dosificación , Estradiol/efectos adversos , Posmenopausia , Adulto , Anciano , Biopsia , Método Doble Ciego , Quimioterapia Combinada , Hiperplasia Endometrial/inducido químicamente , Hiperplasia Endometrial/epidemiología , Hiperplasia Endometrial/patología , Endometrio/patología , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Persona de Mediana Edad , Resultado del Tratamiento , Hemorragia Uterina/epidemiologíaRESUMEN
The assessment of endometrial safety is one of the key requirements for the clinical development of new products for hormone therapy (HT) to treat menopausal symptoms in women who have a uterus. Both the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) provide detailed guidance on the requirements for the evaluation of biopsies to prove endometrial safety. However, there are some discrepancies between the European and the US requirements, making it difficult to fulfil both guidelines simultaneously. In order to facilitate multinational clinical trials performed within clinical programs to develop novel HT products, we developed an approach considering both guidance documents as far as possible and proposed solutions for issues that are inconsistently described in these guidelines. A table with the required sample sizes is given. Our recommendation for a unified approach for the estimation of the hyperplasia rate for hormone therapies fulfils the intent of the recommendations of both the FDA and the EMA and thus leads to a globally harmonized drug development for hormone therapies.
Asunto(s)
Biopsia , Hiperplasia Endometrial , Endometrio , Terapia de Reemplazo de Estrógeno/efectos adversos , Posmenopausia , Biopsia/métodos , Biopsia/normas , Hiperplasia Endometrial/clasificación , Hiperplasia Endometrial/etiología , Hiperplasia Endometrial/patología , Hiperplasia Endometrial/prevención & control , Endometrio/efectos de los fármacos , Endometrio/patología , Terapia de Reemplazo de Estrógeno/métodos , Europa (Continente) , Femenino , Humanos , Agencias Internacionales , Administración del Tratamiento Farmacológico/organización & administración , Guías de Práctica Clínica como Asunto , Medición de Riesgo/métodos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
A variety of fumed oxides such as silica, alumina, titania, silica/alumina (SA), silica/titania (ST), and alumina/silica/titania (AST) were characterized. These oxides have different specific surface areas and different primary particle composition in the bulk and at the surface. These materials were studied by FTIR, NMR, Auger electron spectroscopy, one-pass temperature-programmed desorption with mass spectrometry control (OP TPDMS), microcalorimetry, and nitrogen adsorption. Nonlinear changes in the surface content of alumina in SA and AST and titania in ST and AST samples with increasing oxide content along with simultaneous changes in their specific surface area cause complex dependencies of the heat of immersion in water and desorption of water on heating on the structural parameters. Simultaneous analysis of changes in the surface phase composition, in the concentration of hydroxyls, and in the structural characteristics reveals that at a low content of the second phase the structural characteristics (e.g., S(BET)) are predominant; however, at a large content of these oxides the phase composition plays a more important role.