RESUMO
CONTEXT: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. OBJECTIVE: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. DESIGN AND SETTING: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. PATIENTS: A total of 358 patients with medically naive acromegaly (GH >5 µg/L or GH nadir ≥1 µg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. INTERVENTIONS: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5µg/L and/or IGF-1 was above the upper limit of normal. MAIN OUTCOME MEASURE: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 µg/L and normal IGF-1) at month 12. RESULTS: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 µg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). CONCLUSIONS: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
Assuntos
Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Octreotida/uso terapêutico , Somatostatina/análogos & derivados , Acromegalia/etiologia , Adenoma/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Somatostatina/uso terapêutico , Equivalência Terapêutica , Adulto JovemRESUMO
CONTEXT: Pasireotide (SOM230) is a novel multireceptor ligand somatostatin analog with affinity for somatostatin receptor subtypes sst(1-3) and sst(5). Because most GH-secreting pituitary adenomas express sst(2) and sst(5), pasireotide has the potential to be more effective than the sst(2)-preferential somatostatin analogs octreotide and lanreotide. OBJECTIVE: Our objective was to evaluate the efficacy and safety of three different doses of pasireotide in patients with acromegaly. DESIGN: We conducted a phase II, randomized, multicenter, open-label, three-way, crossover study. PATIENTS: Sixty patients with acromegaly, defined by a 2-h five-point mean GH level higher than 5 microg/liter, lack of suppression of GH to less than 1 microg/liter after oral glucose tolerance test, and elevated IGF-I for age- and sex-matched controls. Patients could have had previous surgery, radiotherapy, and/or medical therapy or no previous treatment. INTERVENTION: After treatment with octreotide 100 microg s.c. three times daily for 28 d, each patient received pasireotide 200, 400, and 600 microg s.c. twice daily in random order for 28 d. MAIN OUTCOME MEASURE: A biochemical response was defined as a reduction in GH to no more than 2.5 microg/liter and normalization of IGF-I to age- and sex-matched controls. RESULTS: After 4 wk of octreotide, 9% of patients achieved a biochemical response. After 4 wk of pasireotide 200-600 microg s.c. bid, 19% of patients achieved a biochemical response, which increased to 27% after 3 months of pasireotide; 39% of patients had a more than 20% reduction in pituitary tumor volume. Pasireotide was generally well tolerated. CONCLUSIONS: Pasireotide is a promising treatment for acromegaly. Larger studies of longer duration evaluating the efficacy and safety of pasireotide in patients with acromegaly are ongoing.
Assuntos
Acromegalia/tratamento farmacológico , Somatostatina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Neoplasias Hipofisárias/patologia , Somatostatina/efeitos adversos , Somatostatina/farmacocinética , Somatostatina/uso terapêutico , Adulto JovemRESUMO
OBJECTIVES: Our purpose was to investigate whether differences exist in the values and temporal evolution of mean diffusivity (
Assuntos
Isquemia Encefálica/patologia , Encéfalo/patologia , Acidente Vascular Cerebral/patologia , Idoso , Idoso de 80 Anos ou mais , Anisotropia , Isquemia Encefálica/complicações , Imagem de Difusão por Ressonância Magnética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Fatores de TempoAssuntos
Acidente Vascular Cerebral/diagnóstico , Análise Custo-Benefício , Humanos , Imageamento por Ressonância Magnética/economia , Imageamento por Ressonância Magnética/normas , Sensibilidade e Especificidade , Acidente Vascular Cerebral/economia , Tomografia Computadorizada por Raios X/economia , Tomografia Computadorizada por Raios X/normas , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate the hypothesis that idiopathic intracranial hypertension is associated with diffuse brain oedema, using quantitative magnetic resonance imaging. METHODS: Values for the mean diffusivity of water (
Assuntos
Edema Encefálico/complicações , Edema Encefálico/patologia , Imagem de Difusão por Ressonância Magnética , Epêndima/patologia , Pseudotumor Cerebral/etiologia , Pseudotumor Cerebral/patologia , Adolescente , Adulto , Edema Encefálico/fisiopatologia , Epêndima/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Pseudotumor Cerebral/fisiopatologiaRESUMO
We have developed a closed chest animal model that allows noninvasive monitoring of cardiac high energy phosphate metabolism before, during, and for at least 3 weeks after a myocardial infarction. Ten beagles underwent 2 h of coronary occlusion followed by 3 weeks of reperfusion. Myocardial high energy phosphates from 12-ml voxels were noninvasively tracked using 31P two-dimensional chemical shift imaging. Gadolinium enhanced 1H MRI identified the zone at risk, and radioactive microspheres assessed regional blood flow and partition coefficients. Occlusion of the left anterior descending coronary artery produced infarcts that were 13.7+/-8.8% (mean+/-SD) of the left ventricular volume. Rapid changes in the phosphocreatine and inorganic phosphate levels were observed during occlusion, whereas adenosine triphosphate levels decreased more slowly. All metabolites recovered to base-line levels 2 weeks after occluder release. Multiple inorganic phosphate peaks in the infarct voxel spectra indicated that more than one metabolically compromised tissue zone developed during occlusion and reperfusion. Microsphere data indicating three distinct blood flow zones during ischemia and reperfusion (<0.3, 0.3-0.75, and >0.75 ml/min/g) supported the grouping of pH values into three distinct metabolic distributions.