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2.
Horm Res Paediatr ; 91(1): 56-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30114684

RESUMO

BACKGROUND: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. CONCLUSION: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.


Assuntos
Hiperinsulinismo Congênito/diagnóstico por imagem , Hiperinsulinismo Congênito/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Tomografia por Emissão de Pósitrons , Somatostatina/análogos & derivados , Tomografia Computadorizada por Raios X , Hiperinsulinismo Congênito/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pancreatopatias/induzido quimicamente , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/terapia , Peptídeos Cíclicos/efeitos adversos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Receptores Sulfonilureia/genética
3.
J Nucl Med ; 60(3): 377-385, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30115686

RESUMO

To date, limited data are available concerning peptide receptor radionuclide therapy (PRRT) of grade 3 (G3) neuroendocrine neoplasms (NENs) with a Ki-67 proliferation index of greater than 20%. The purpose of this study was to analyze the long-term outcome, efficacy, and safety of PRRT in patients with somatostatin receptor (SSTR)-expressing G3 NENs. Methods: A total of 69 patients (41 men; age, 28-81 y) received PRRT with 177Lu- or 90Y-labeled somatostatin analogs (DOTATATE or DOTATOC). Twenty-two patients had radiosensitizing chemotherapy. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT, including a subgroup analysis for patients with a Ki-67 index of less than or equal to 55% and a Ki-67 index of greater than 55%. Treatment response was evaluated according to RECIST 1.1 as well as molecular imaging criteria (European Organization for Research and Treatment of Cancer). Short- and long-term toxicity was documented (Common Terminology Criteria for Adverse Events, v 5.0) using a structured database (comprising >250 items per patient) and retrospectively analyzed. Results: Forty-six patients had pancreatic NENs, 11 had unknown primary cancer, 6 had midgut NENs, 3 had gastric NENs, and 3 had rectal NENs. The median follow-up was 94.3 mo. The median PFS was 9.6 mo, and the median OS was 19.9 mo. For G3 NENs with a Ki-67 index of less than or equal to 55% (n = 53), the median PFS was 11 mo and the median OS was 22 mo. Patients with a Ki-67 index of greater than 55% (n = 11) had a median PFS of 4 mo and a median OS of 7 mo. For patients with positive SSTR imaging but no 18F-FDG uptake, the median PFS was 24 mo and the median OS was 42 mo. A significant difference was found for both PFS and OS, with median PFS of 16 mo and 5 mo and median OS of 27 mo and 9 mo for an SUVmax of greater than 15.0 and an SUVmax of less than or equal to 15.0, respectively, on SSTR PET. In the group with 18F-FDG uptake scored as 3 or 4, the median PFS was 7.1 mo and the median OS was 17.2 mo. In the group with 18F-FDG uptake scored as 0-2, the median PFS was 24.3 mo and the median OS was 41.6 mo. PRRT was well tolerated by all patients; no grade 3 or grade 4 hematotoxicity occurred, and no clinically significant decline in renal function was observed. There was no hepatotoxicity. Conclusion: PRRT was tolerated well, without significant adverse effects, and was efficacious in G3 NENs; the clinical outcome was promising, especially in patients with a Ki-67 index of less than or equal to 55% and even in patients for whom chemotherapy had failed. Baseline 18F-FDG along with SSTR molecular imaging was useful for stratifying G3 NEN patients with high uptake on SSTR PET/CT and no or minor 18F-FDG avidity-a mismatch pattern that was associated with a better long-term prognosis.


Assuntos
Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Receptores de Somatostatina/metabolismo , Segurança , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Estudos Retrospectivos , Somatostatina/química , Somatostatina/metabolismo , Análise de Sobrevida , Resultado do Tratamento
4.
J Clin Endocrinol Metab ; 104(3): 883-891, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30371791

RESUMO

Context: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas. Objective: To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations. Design: Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts. Patients: A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo). Main Outcome Measures: Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria. Results: The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study. Conclusions: Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension.


Assuntos
Dopamina/administração & dosagem , Antagonistas de Hormônios/administração & dosagem , Hormônio do Crescimento Humano/antagonistas & inibidores , Hipófise/efeitos dos fármacos , Somatostatina/administração & dosagem , Adolescente , Adulto , Dopamina/efeitos adversos , Dopamina/análogos & derivados , Dopamina/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Antagonistas de Hormônios/efeitos adversos , Antagonistas de Hormônios/farmacocinética , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Injeções Subcutâneas , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Hipófise/metabolismo , Neoplasias Hipofisárias/tratamento farmacológico , Prolactina/sangue , Somatostatina/efeitos adversos , Somatostatina/análogos & derivados , Somatostatina/farmacocinética , Adulto Jovem
5.
Invest New Drugs ; 37(4): 763-770, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30536151

RESUMO

Lanreotide autogel is a long-acting somatostatin analogue with proven efficacy and safety in patients with well-differentiated (WD) gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) in a prior randomized phase III trial (CLARINET). However, the CLARINET study only enrolled patients with Ki-67 index <10%, and few patients of Asian ethnicity were included. We retrospectively analyzed the efficacy and safety of lanreotide in Korean patients with GEP-NETs in the daily practice setting. Between January 2015 and May 2018, 64 patients with metastatic WD GEP-NETs received lanreotide at Asan Medical Center, Seoul, Korea. Of them, 45 (70.3%) patients who received lanreotide as monotherapy were included in the current analysis. The most common primary tumor site was the pancreas (n = 22, 48.9%), followed by the rectum (10, 22.2%) and the small bowel (7, 15.6%). According to RECIST v1.1, a partial response was achieved in one patient (2.2%) and stable disease was achieved in 40 patients (88.9%). The median progression-free survival (PFS) was 16.4 months (95% confidence interval, 9.5-23.3 months). There were no differences in PFS according to the primary tumor site (p = 0.77). Hepatic tumor volume > 25% and prior systemic therapy were significantly associated with poorer PFS in the multivariate analysis. Lanreotide is well-tolerated and effective for Korean patients with GEP-NETs in the daily practice setting.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Peptídeos Cíclicos/efeitos adversos , Intervalo Livre de Progressão , República da Coreia , Estudos Retrospectivos , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Neoplasias Gástricas/patologia , Carga Tumoral , Adulto Jovem
6.
Dig Liver Dis ; 51(5): 689-694, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30314949

RESUMO

BACKGROUND: Somatostatin analogs are the backbone of neuroendocrine neoplasms treatment. Biliary stone disease is a potentially severe adverse event of somatostatin analogs: an increased incidence has been reported in somatostatin analogs-treated acromegalic patients, but studies on patients with neuroendocrine neoplasms are lacking. AIMS: To evaluate biliary stone disease incidence and associated factors in a large series of patients treated with somatostatin analogs for neuroendocrine neoplasms. METHODS: A prospectively-collected database of patients with a diagnosis of neuroendocrine neoplasms of any grade and site, treated with somatostatin analogs at our Institution between 1995 and 2017, was retrospectively analyzed. Patients' demographics and disease characteristics were analyzed to evaluate the incidence and the factors related to biliary stone disease. RESULTS: Three-hundred patients were included; 101 (33.7%) patients underwent cholecystectomy before starting somatostatin analogs. Among 164 patients with gallbladder in situ and no history of stone disease, 60 (36.6%) developed gallstones after a mean of 36.7 months (range 1-239) from treatment start with a mean yearly incidence of 8.73%. Previous cholecystectomy was associated with a lower rate of development of gallstones (p < 0.001) or related complications (p = 0.017). CONCLUSION: We observed a high incidence of biliary stone disease in patients treated with somatostatin analogs-treated for neuroendocrine neoplams. Previous cholecystectomy was the only factor associated with a lower occurrence of biliary stone disease.


Assuntos
Cálculos Biliares/induzido quimicamente , Tumores Neuroendócrinos/terapia , Somatostatina/análogos & derivados , Somatostatina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistectomia , Bases de Dados Factuais , Feminino , Cálculos Biliares/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/uso terapêutico , Estudos Retrospectivos , Somatostatina/uso terapêutico , Adulto Jovem
7.
Expert Opin Drug Saf ; 18(1): 1-10, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30582380

RESUMO

INTRODUCTION: Lanreotide autogel is a synthetic somatostatin analogue which has been FDA and EMA approved for unresectable, well to moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumor. Its action is mediated by its affinity to somatostatin receptors, especially sst2 and sst5 receptors. Its longer half-life offers the convenience of 4-week dosing over the need for frequent injections of short-acting somatostatin analogues. Areas covered: Lanreotide ATG offers progression-free survival benefit in locally advanced or metastatic neuroendocrine tumor (NET) compared to placebo, reflecting a strong antiproliferative signal. As lanreotide is commonly used for management of NET, it is imperative to recognize and appropriately manage any drug-related toxicities. In this review, we will provide an overview of the toxicity with lanreotide and its management. Expert opinion: Lanreotide is highly effective in managing carcinoid symptoms and has a robust anti-tumor effect in NET. Overall, it is well tolerated with low rates of treatment discontinuation due to toxicity. It's toxicity profile is mostly predictable, and patients should be informed of the transient nature of some of the upfront toxicities.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Somatostatina/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Intervalo Livre de Doença , Humanos , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/farmacologia , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/farmacologia , Neoplasias Gástricas/patologia
8.
JAMA ; 320(19): 2010-2019, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30422235

RESUMO

Importance: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation in both kidneys and loss of renal function, eventually leading to a need for kidney replacement therapy. There are limited therapeutic management options. Objective: To examine the effect of the somatostatin analogue lanreotide on the rate of kidney function loss in patients with later-stage ADPKD. Design, Setting, and Participants: An open-label randomized clinical trial with blinded end point assessment that included 309 patients with ADPKD from July 2012 to March 2015 at 4 nephrology outpatient clinics in the Netherlands. Eligible patients were 18 to 60 years of age and had an estimated glomerular filtration rate (eGFR) of 30 to 60 mL/min/1.73 m2. Follow-up of the 2.5-year trial ended in August 2017. Interventions: Patients were randomized to receive either lanreotide (120 mg subcutaneously once every 4 weeks) in addition to standard care (n = 153) or standard care only (target blood pressure <140/90 mm Hg; n = 152). Main Outcomes and Measures: Primary outcome was annual change in eGFR assessed as slope through eGFR values during the 2.5-year treatment phase. Secondary outcomes included change in eGFR before vs after treatment, incidence of worsening kidney function (start of dialysis or 30% decrease in eGFR), change in total kidney volume and change in quality of life (range: 1 [not bothered] to 5 [extremely bothered]). Results: Among the 309 patients who were randomized (mean [SD] age, 48.4 [7.3] years; 53.4% women), 261 (85.6%) completed the trial. Annual rate of eGFR decline for the lanreotide vs the control group was -3.53 vs -3.46 mL/min/1.73 m2 per year (difference, -0.08 [95% CI, -0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (-3.58 vs -3.45; difference, -0.13 mL/min/1.73 m2 per year [95% CI, -1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, -0.03 units per year [95% CI, -0.13 to 0.08]; P = .67). The rate of growth in total kidney volume was lower in the lanreotide group than the control group (4.15% vs 5.56%; difference, -1.33% per year [95% CI, -2.41% to -0.24%]; P = .02). Adverse events in the lanreotide vs control group included injection site discomfort (32% vs 0.7%), injection site papule (5.9% vs 0%), loose stools (91% vs 6.6%), abdominal discomfort (79% vs 20%), and hepatic cyst infections (5.2% vs 0%). Conclusions and Relevance: Among patients with later-stage autosomal dominant polycystic kidney disease, treatment with lanreotide compared with standard care did not slow the decline in kidney function over 2.5 years of follow-up. These findings do not support the use of lanreotide for treatment of later-stage autosomal dominant polycystic kidney disease. Trial Registration: ClinicalTrials.gov Identifier: NCT01616927.


Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Rim Policístico Autossômico Dominante/tratamento farmacológico , Somatostatina/análogos & derivados , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/efeitos adversos , Rim Policístico Autossômico Dominante/fisiopatologia , Qualidade de Vida , Diálise Renal , Método Simples-Cego , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
9.
Drugs Today (Barc) ; 54(8): 457-465, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30209440

RESUMO

Carcinoid tumors are rare and usually slow-growing. Some patients with advanced metastatic disease however can develop symptoms of carcinoid syndrome, which results in debilitating diarrhea and flushing. Many treatments including chemotherapy were tried unsuccessfully in the past to treat this syndrome. The symptoms of carcinoid syndrome are thought to be related to the ability of the tumors to produce serotonin. The discovery that the production of this hormone can be inhibited by somatostatin led to the development of somatostatin analogues octreotide and lanreotide, which differ from native somatostatin in that they have a longer half-life. These compounds have shown dramatic responses in symptom control and reduction of serotonin metabolites including urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. This review researches the origins of carcinoid tumors, the development of lanreotide as a treatment and future directions for the treatment of carcinoid syndrome.


Assuntos
Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Síndrome do Carcinoide Maligno/tratamento farmacológico , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Antineoplásicos/efeitos adversos , Tumor Carcinoide/epidemiologia , Tumor Carcinoide/patologia , Humanos , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/epidemiologia , Estadiamento de Neoplasias , Octreotida/efeitos adversos , Peptídeos Cíclicos/efeitos adversos , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Resultado do Tratamento
10.
Clin Nucl Med ; 43(11): 864-866, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30222684

RESUMO

Neuroendocrine tumors have a propensity to metastasize, but rarely to the orbits. A 69-year-old woman with history of neuroendocrine tumor of pancreatic primary underwent routine follow-up In-pentetreotide (OctreoScan) imaging, with 24-hour whole-body planar images showing subtle right periorbital tracer uptake that localized to extraocular muscles on subsequent SPECT/CT. Orbital MRI further defined the location of these highly suspicious orbital metastases, which were treated with external radiation, with follow-up MRI showing decreased size of the orbital metastases. Early identification and treatment of orbital metastases is critical to help preserve vision and quality of life.


Assuntos
Neoplasias Induzidas por Radiação/secundário , Tumores Neuroendócrinos/secundário , Neoplasias Orbitárias/secundário , Compostos Radiofarmacêuticos/efeitos adversos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/efeitos adversos , Somatostatina/análogos & derivados , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética , Neoplasias Induzidas por Radiação/etiologia , Tumores Neuroendócrinos/etiologia , Neoplasias Orbitárias/etiologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Somatostatina/efeitos adversos
11.
Eur J Endocrinol ; 179(5): 269-277, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30076159

RESUMO

OBJECTIVE: to assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia. DESIGN: The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks. METHODS: 59 out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤ 1.2 x the Upper Limit of Normal (ULN)) at 48-weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT). RESULTS: At the end of the study median IGF-I was 0.98 x ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and 9 patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = -0.37, P < 0.005). CONCLUSIONS: PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a fifty percent pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.


Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Fator de Crescimento Insulin-Like I/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Substituição de Medicamentos , Seguimentos , Teste de Tolerância a Glucose , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Insulina/sangue , Octreotida/uso terapêutico , Estudos Prospectivos , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Resultado do Tratamento
12.
Endocrinol Metab Clin North Am ; 47(3): 615-625, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30098719

RESUMO

Peptide receptor radionuclide therapy is a form of systemic radiotherapy shown to be effective in treating neuroendocrine tumors expressing somatostatin receptors. The NETTER-1 trial was the first randomized phase III clinical trial evaluating a radiolabeled somatostatin analog, and demonstrated significant improvement in progression-free survival among patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE versus high-dose octreotide. This article discusses the evolution of peptide receptor radionuclide therapy, side effects, and potential future treatment approaches.


Assuntos
Tumores Neuroendócrinos/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Radioterapia/métodos , Receptores de Peptídeos , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Humanos , Compostos Radiofarmacêuticos/efeitos adversos , Radioterapia/tendências , Receptores de Somatostatina/efeitos dos fármacos , Somatostatina/efeitos adversos
13.
Br J Nurs ; 27(13): 738-744, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29995506

RESUMO

Somatostatin analogues (SSA) are a common treatment for some forms of neuroendocrine tumours (NETs). Patients report a variety of side effects after starting these drugs, so in most cases they require a lot of nutritional input. The authors used an online survey to invite responses from patients worldwide to determine the extent of reported side effects. Patients were asked which SSA they were taking and how they rated the severity of their side effects. They were provided with a list of 11 options to choose from, but not given any guidance or a definition of terms. The most commonly reported side effect was constipation (85%), with 8.6% of these respondents rating its severity as 10/10. The survey found that many self-reported side effects from the use of SSAs were experienced more frequently than previous clinical studies or the patient information leaflets reported. As this was an online survey, so the findings are limited in that first, this was a self-selected sample of patients and second, patients were able to respond more than once.


Assuntos
Tumores Neuroendócrinos/tratamento farmacológico , Somatostatina/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Prevalência , Somatostatina/uso terapêutico
14.
Value Health ; 21(7): 874-880, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30005760

RESUMO

BACKGROUND: Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted. OBJECTIVES: To conduct the first network meta-analysis simultaneously comparing all available drugs used in acromegaly treatment so as to provide more robust evidence in this field. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration recommendations (PROSPERO database under the registration number CRD42017059880). The electronic searches were conducted in PubMed (MEDLINE), Scopus, and Web of Science databases. Randomized controlled trials comparing any drug for the treatment of acromegaly head-to-head or versus placebo were included. Outcomes concerning the efficacy and safety of treatments were evaluated. The statistical analyses were performed using Aggregate Data Drug Information System version 1.16.8 (drugis.org, Groningen, The Netherlands). RESULTS: The initial search retrieved 2059 articles. Of these, 10 randomized controlled trials were included in a qualitative analysis and 7 in a quantitative analysis. The network meta-analysis for the efficacy outcome (number of patients achieving insulinlike growth factor 1 control) showed that pegvisomant and lanreotide autogel were statistically superior to placebo (odds ratio [95% credible interval] 0.06 [0.00-0.55] and 0.09 [0.01-0.88]). No further differences were found. The probability rank indicated that pegvisomant and pasireotide have the highest probabilities (33% and 34%, respectively) of being the best therapeutic options. No major side effects were noted. CONCLUSIONS: Pegvisomant is still a good option for acromegaly treatment, but pasireotide seems to be a promising alternative. Nevertheless, other important key factors such as drug costs and effectiveness (real-world results) should be taken into account when selecting acromegaly treatment.


Assuntos
Acromegalia/tratamento farmacológico , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/metabolismo , Peptídeos Cíclicos/uso terapêutico , Receptores da Somatotropina/antagonistas & inibidores , Somatostatina/análogos & derivados , Acromegalia/metabolismo , Acromegalia/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Antagonistas de Hormônios/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/efeitos adversos , Receptores da Somatotropina/metabolismo , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
15.
Expert Rev Gastroenterol Hepatol ; 12(7): 723-731, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29923433

RESUMO

BACKGROUND: Patients with advanced well-differentiated neuroendocrine tumours (Wd-NETs) are commonly treated with somatostatin analogues (SSAs). Some patients may develop SSA-related side effects such as pancreatic exocrine insufficiency (PEI). METHODS: In this prospective, observational study, the frequency of SSA-induced PEI in 50 sequential patients with advanced Wd-NETs treated with SSAs was investigated. Toxicity was assessed monthly and faecal elastase-1 (FE1) and quality of life (QoL) were assessed 3-monthly. RESULTS: The median age was 65.8 years, 58% were male and the majority (92%) of patients had metastatic disease; patients received 4-weekly long acting octreotide (60%) or lanreotide (40%). Twelve patients (24%) developed SSA-related PEI after a median of 2.9 months from SSA initiation; FE1 was a reliable screening tool for PEI, especially in symptomatic (abdominal bloating, flatulence and/or diarrhea) patients (risk ratio 8.25 (95% confidence interval 1.15-59.01)). Most of these patients (11/12; 92%) required PERT. Other SSA-related adverse events (any grade) included flatulence (50%), abdominal pain (32%), diarrhoea (30%) and fatigue (20%). Development of PEI did not significantly worsen overall QoL, however gastrointestinal symptoms and diarrhoea were increased. CONCLUSION: This study demonstrated that PEI occurs at a higher rate than previously reported; clinicians need to diagnose and treat this SSA-related adverse-event which occurs in 1 in 4 patients with Wd-NETs treated with SSAs. Screening with FE1 in symtomatic patients is recommend.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Insuficiência Pancreática Exócrina/induzido quimicamente , Octreotida/efeitos adversos , Peptídeos Cíclicos/efeitos adversos , Somatostatina/análogos & derivados , Idoso , Biomarcadores/metabolismo , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Diferenciação Celular , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/enzimologia , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Elastase Pancreática/metabolismo , Estudos Prospectivos , Qualidade de Vida , Fatores de Risco , Somatostatina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
16.
J Nucl Med ; 59(11): 1699-1705, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29653971

RESUMO

Radiolabeled somatostatin analog therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogs in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-humans study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analog, 177Lu-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (177Lu-DOTA-EB-TATE). Methods: Eight patients (6 men and 2 women; age range, 27-61 y) with advanced metastatic NETs were recruited. Five patients received a single dose, 0.35-0.70 GBq (9.5-18.9 mCi), of 177Lu-DOTA-EB-TATE and underwent serial whole-body planar and SPECT/CT scans at 2, 24, 72, 120, and 168 h after injection. The other 3 patients received intravenous injection of 0.28-0.41 GBq (7.5-11.1 mCi) of 177Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24, and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Results: Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177Lu-DOTATATE, 177Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved a 7.9-fold increase of tumor dose delivery. The total-body effective doses were 0.205 ± 0.161 mSv/MBq for 177Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177Lu-DOTA-EB-TATE compared with those receiving 177Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin-binding moiety, 177Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NETs as well as significantly increased accumulation in the kidneys and red marrow. It has great potential to be used in peptide receptor radionuclide therapy for NETs with lower dose and less frequency of administration.


Assuntos
Complexos de Coordenação/uso terapêutico , Tumores Neuroendócrinos/radioterapia , Tumores Neuroendócrinos/secundário , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Somatostatina/análogos & derivados , Adulto , Complexos de Coordenação/efeitos adversos , Complexos de Coordenação/farmacocinética , Azul Evans , Feminino , Humanos , Rim/efeitos da radiação , Lutécio/efeitos adversos , Lutécio/farmacocinética , Lutécio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Octreotida/efeitos adversos , Octreotida/farmacocinética , Octreotida/uso terapêutico , Compostos Organometálicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radioisótopos/efeitos adversos , Radioisótopos/farmacocinética , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Dosagem Radioterapêutica , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Somatostatina/efeitos adversos , Somatostatina/metabolismo , Somatostatina/farmacocinética , Somatostatina/uso terapêutico , Distribuição Tecidual , Imagem Corporal Total
17.
Diabetes ; 67(6): 1173-1181, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29540491

RESUMO

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/efeitos adversos , Insulina Regular Humana/análogos & derivados , Fígado/efeitos dos fármacos , Absorção Fisiológica/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Cães , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Gluconeogênese/efeitos dos fármacos , Técnica Clamp de Glucose , Glicosilação , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Infusões Intravenosas , Insulina Regular Humana/administração & dosagem , Insulina Regular Humana/efeitos adversos , Insulina Regular Humana/farmacocinética , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Distribuição Aleatória , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos
18.
Curr Drug Metab ; 19(10): 876-882, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29595102

RESUMO

BACKGROUND: Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible. METHODS AND RESULTS: Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed. CONCLUSION: Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.


Assuntos
Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Animais , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Somatostatina/efeitos adversos , Somatostatina/farmacocinética , Somatostatina/farmacologia , Somatostatina/uso terapêutico
19.
HPB (Oxford) ; 20(5): 418-422, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29398424

RESUMO

BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 µg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.


Assuntos
Pancreatectomia/efeitos adversos , Fístula Pancreática/prevenção & controle , Pancreaticoduodenectomia/efeitos adversos , Somatostatina/análogos & derivados , Idoso , Estudos de Casos e Controles , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Fístula Pancreática/diagnóstico por imagem , Fístula Pancreática/etiologia , Estudos Prospectivos , Fatores de Risco , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
20.
Cancer Imaging ; 18(1): 3, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29361984

RESUMO

BACKGROUND: To evaluate the effects of long-acting somatostatin analogue (SSA) therapy on 68Ga-DOTA-octreotate (GaTate) uptake at physiological and metastatic sites in neuroendocrine tumour (NET) patients. METHODS: Twenty-one patients who underwent GaTate PET/CT before and after commencement of SSA therapy were reviewed. Maximum standardized uptake values (SUVmax) were measured in normal organs. Changes in uptake of 49 metastatic lesions in 12 patients with stable disease were also compared. Serum chromogranin-A (CgA) levels were available for correlation between scans in 17/21 patients. RESULTS: Mean thyroid, spleen and liver SUVmax decreased significantly following SSA therapy from a baseline of 5.9 to 3.5, 30.3 to 23.1 and 10.3 to 8.0, respectively (p = < 0.0001 for all). Pituitary SUVmax increased from 10.2 to 11.0 (p = 0.004) whereas adrenal and salivary gland SUVmax did not change. Tumour SUVmax increased in 7 of 12 patients with stable disease; CgA was stable or decreasing in 5 of these patients. 30/49 (61%) metastatic lesions had an increase in SUVmax and lesion-to-liver uptake ratio increased in 40/49 (82%) following SSA therapy. CONCLUSION: Long-acting SSA therapy decreases GaTate uptake in the thyroid, spleen and liver but in most cases increases intensity of uptake within metastases. This has significant implications for interpretation of GaTate PET/CT following commencement of therapy as increased intensity alone may not represent true progression. Our findings also suggest pre-dosing with SSA prior to PRRT may enable higher doses to be delivered to tumour whilst decreasing dose to normal tissues.


Assuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Octreotida/análogos & derivados , Compostos Organometálicos/farmacocinética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/normas , Compostos Radiofarmacêuticos/farmacocinética , Somatostatina/efeitos adversos , Adulto , Idoso , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Octreotida/farmacocinética , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Distribuição Tecidual
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