Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
Breast Cancer Res ; 23(1): 8, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33451345

RESUMEN

BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/etiología , Adulto , Anciano , Anciano de 80 o más Años , Androstadienos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Manejo de la Enfermedad , Everolimus/administración & dosificación , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Resultado del Tratamiento
2.
Diab Vasc Dis Res ; 17(6): 1479164120975256, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33307785

RESUMEN

OBJECTIVE: It is well established that higher low-density lipoprotein (LDL)-cholesterol levels are associated with increased cardiovascular risk. We analyzed whether effects of empagliflozin on cardiovascular outcomes varied by different LDL-cholesterol levels at baseline in EMPA-REG OUTCOME. METHODS: Participants with type 2 diabetes and high cardiovascular risk received empagliflozin (10/25 mg) or placebo in addition to standard of care. We investigated the time to first 3P-MACE, cardiovascular death, hospitalization for heart failure (HHF) and all-cause mortality for empagliflozin versus placebo between baseline LDL-cholesterol categories <1.8, 1.8-<2.2, 2.2- <2.6, 2.6-3.0, and > 3.0 mmol/L, by a Cox regression including the interaction of baseline LDL-cholesterol category and treatment. RESULTS: Of the 7020 participants randomized and treated, 81.0% received lipid lowering therapy (77.0% statins). Mean ± SD LDL-cholesterol was 2.2 ± 0.9 mmol/L, and 38%/18%, had LDL-cholesterol <1.8/>3.0 mmol/L. Age, BMI, and HbA1c levels were balanced between the LDL-cholesterol subgroups, but those in the lowest versus highest group, had more coronary artery disease (83.0% vs 59.9%) and statin treatment (88.2% vs 50.9%). Empagliflozin consistently reduced all outcomes across LDL-cholesterol categories (all interaction p-values > 0.05). CONCLUSION: The beneficial cardiovascular effects of empagliflozin was consistent across higher and lower LDL-cholesterol levels at baseline.


Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/efectos adversos , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Glucósidos/efectos adversos , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Estudios Prospectivos , Medición de Riesgo , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Factores de Tiempo , Resultado del Tratamiento
3.
Diab Vasc Dis Res ; 12(2): 90-100, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25589482

RESUMEN

Given the multi-faceted pathogenesis of atherosclerosis in type 2 diabetes mellitus (T2DM), it is likely that interventions to mitigate this risk must address cardiovascular (CV) risk factors beyond glucose itself. Sodium glucose cotransporter-2 (SGLT-2) inhibitors are newer antihyperglycaemic agents with apparent multiple effects. Inherent in their mode of action to decrease glucose reabsorption by the kidneys by increasing urinary glucose excretion, these agents improve glycaemic control independent of insulin secretion with a low risk of hypoglycaemia. In this review, we outline those CV risk factors that this class appears to influence and provide the design features and trial characteristics of six ongoing outcome trials involving more than 41,000 individuals with T2DM. Those risk factors beyond glucose that can potentially be modulated positively with SGLT-2 inhibitors include blood pressure, weight, visceral adiposity, hyperinsulinaemia, arterial stiffness, albuminuria, circulating uric acid levels and oxidative stress. On the other hand, small increases in low-density lipoprotein (LDL)-cholesterol levels have also been observed for the class, which theoretically might offset some of these benefits. The potential translational impact of these effects is being tested with outcome trials, also reviewed in this article, powered to assess both macrovascular as well as certain microvascular outcomes in T2DM. These are expected to begin to report in late 2015.


Asunto(s)
Glucemia/efectos de los fármacos , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Túbulos Renales Proximales/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucemia/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/fisiopatología , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Hipoglucemiantes/efectos adversos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/fisiopatología , Terapia Molecular Dirigida , Eliminación Renal/efectos de los fármacos , Reabsorción Renal/efectos de los fármacos , Medición de Riesgo , Factores de Riesgo , Transportador 2 de Sodio-Glucosa/metabolismo , Resultado del Tratamiento
4.
Clin Endocrinol (Oxf) ; 56(3): 329-34, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11940044

RESUMEN

OBJECTIVE: To investigate the GH response to glucagon in adult patients with GH deficiency and in controls compared with the GH response to the insulin tolerance test (ITT) in patients with GH deficiency and to determine whether the use of glucagon results in a diagnostic utility test. PATIENTS AND DESIGN: Seventy-three patients with adult GH deficiency and organic hypothalamic-pituitary disease were recruited, along with 46 controls. The patients were divided into five groups according to the number of associated hormone deficiencies present. MEASUREMENTS: Hypopituitary subjects underwent assessment of GH secretory status by the ITT, the glucagon test and measurement of serum IGF-I concentration. Controls underwent the glucagon test. After the ITT, glucose and GH levels were measured at baseline, 30, 60 and 90 minutes, and after glucagon at baseline, 90, 120, 150, 180, 210 and 240 minutes. RESULTS: The highest GH value after the ITT in the patient group was 3 microg/l (0.76 +/- 0.82 microg/l), and after the glucagon test the highest GH peak value was 2.9 microg/l (0.64 +/- 0.79 microg/l). A correlation was found between the GH peak and the progressive number of hormone deficiencies. After the glucagon test, the GH peak obtained in the controls at 180 minutes was 9.8 +/- 4.6 microg/l and, on an individual basis, none of the 46 controls failed to achieve peak GH levels higher than 3 microg/l. In the controls, a negative correlation was observed between the GH response to glucagon and age (r = -0.389, P = 0.0075) and body mass index (r = -0.329, P = 0.0254). The accuracy of the glucagon test for differentiating patients from controls, estimated by receiver operating characteristics (ROC) curve methodology, showed that the cut-off of 3 microg/l for the GH peak provides 100% sensitivity and 100% specificity and is a reliable decision threshold. CONCLUSIONS: The glucagon GH test is reliable and provides a clear separation between GH-deficient and normal adults. A single glucagon test with a cut-off of 3 microg/l for the GH peak is diagnostic of GH deficiency in adults and could be considered and studied as an alternative to the ITT.


Asunto(s)
Glucagón , Hormona de Crecimiento Humana/deficiencia , Adolescente , Adulto , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , Femenino , Hormona de Crecimiento Humana/metabolismo , Humanos , Insulina , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Curva ROC , Sensibilidad y Especificidad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA