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OBJECTIVES: Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long-acting pasireotide during a long-term extension study in patients with CD. DESIGN: Open-label extension to a 12-month Phase III study of long-acting pasireotide in CD (N = 150; NCT01374906). PATIENTS: Patients with mean urinary free cortisol (mUFC) ≤ upper limit of normal (ULN) or receiving clinical benefit at core study end could continue long-acting pasireotide during the extension. RESULTS: Eighty-one of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received ≥ 12 months' treatment during the extension and could transit to a separate pasireotide safety study). mUFC was ≤ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median late-night salivary cortisol was 2.6 × ULN at core baseline and 1.3 × ULN at M36. Clinical improvements were sustained over time. Forty-two (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemia-related AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA1c ) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixty-six (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA1c ≥ 6.5%, FPG ≥ 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment. CONCLUSIONS: Long-acting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective long-term therapy for CD.
Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Somatostatina/análogos & derivados , Hormônio Adrenocorticotrópico/sangue , Síndrome de Cushing/sangue , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/urina , Método Duplo-Cego , Jejum/sangue , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Masculino , Hipersecreção Hipofisária de ACTH/sangue , Hipersecreção Hipofisária de ACTH/urina , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Tempo , Resultado do TratamentoRESUMO
PURPOSE: Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing's disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD. METHODS: Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study ( http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies. RESULTS: At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). Eight patients had completed the 3-year observation period, 53 were ongoing, and 66 had discontinued. Among 31 new-use and 92 prior-use patients with ≥ 1 safety assessment, respectively: 24 (77%) and 37 (40%) had drug-related adverse events (AEs); 7 (23%) and 10 (11%) had serious drug-related AEs. Most common drug-related AEs were nausea (14%), hyperglycemia (11%) and diarrhea (11%); these were more frequently reported in new users and mostly of mild-to-moderate severity. 14 (45%) new-use and 15 (16%) prior-use patients experienced hyperglycemia-related AEs. Mean urinary free cortisol (mUFC) was within normal range at baseline and months 1, 12 and 24, respectively, in: 1/16 (6%), 9/18 (50%), 1/3 (33%) and 0/0 new users; 28/43 (65%), 15/27 (56%), 27/33 (82%) and 12/19 (63%) prior users. CONCLUSIONS: Pasireotide is well tolerated and provides sustained reductions in mUFC during real-world treatment of CD. The lower rate of hyperglycemia-related AEs in prior users suggests that hyperglycemia tends not to deteriorate if effectively managed soon after onset. CLINICAL TRIAL REGISTRATION NUMBER: NCT02310269.
Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Somatostatina/análogos & derivados , Adulto , Feminino , Humanos , Hiperglicemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Hipersecreção Hipofisária de ACTH/fisiopatologia , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Resultado do TratamentoRESUMO
Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90-99% of women and 60-90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40-50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.
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Doenças do Sistema Endócrino/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Humanos , Doenças Hipotalâmicas/etiologia , Infertilidade/etiologia , Masculino , Fatores de Risco , Fatores Sexuais , Doenças da Glândula Tireoide/etiologia , Transplante Autólogo/efeitos adversos , Transplante Homólogo/efeitos adversosRESUMO
Background: Glioblastoma (GBM), the most common malignant brain tumor, is associated with devastating outcomes. IPAX-1 was a multicenter, open-label, single-arm phase I study to evaluate carrier-added 4-L-[131I]iodo-phenylalanine ([131I]IPA) plus external radiation therapy (XRT) in recurrent GBM. Methods: A total of 10 adults with recurrent GBM who had received first-line debulking surgery plus radio-chemotherapy, were randomized to a single-dose regimen (1f; 131I-IPA 2 GBq before XRT); a fractionated parallel dose regimen (3f-p; 3 131I-IPA 670 MBq fractions, in parallel with second-line XRT), or a fractionated sequential dose regimen (3f-s; 3 131I-IPA 670 MBq fractions before and after XRT). Metabolic tumor responses were determined using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography, while single-photon emission computed tomography was used to guide [131I]IPA tumor dosimetry. Results: All dose regimens were well tolerated. Organ-absorbed radiation doses in red marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease was observed in 4 of the 9 patients at 3 months post-treatment (3-month follow-up [FU], 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month FU, 6 patients demonstrated metabolic stable disease. Median progression-free survival was 4.3 months (95% confidence interval [CI]: 3.3-4.5), while median overall survival was 13 months (95% CI: 7.1-27). Conclusions: Single or fractionated doses of [131I]IPA plus XRT were associated with acceptable tolerability and specific tumor targeting in patients with recurrent GBM, warranting further investigation.
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This study was aimed at evaluating the effect of clothing style on bone mass and fractures in 70 postmenopausal nuns residing in a monastery in Naples. Sixty healthy women matched for age, body mass index, and menopausal status were enrolled as controls. Each participant underwent measurement by quantitative ultrasonometry (QUS) using a DBM Sonic Bone Profiler (IGEA S.p.A., Carpi, Modena, Italy) at proximal phalanges, responded to questionnaires regarding lifestyle, calcium intake, medical history, including clinical fragility fractures, and was submitted to routine biochemical assessment. A significant reduction in ultrasonometric parameters of bone mass was found in nuns compared with controls (p from 0.007 to <0.0001). 25-hydroxyvitamin D (25-OH vit D) levels were reduced by more than 50% in nuns (9.8 ± 4.2 vs 23.5 ± 5.7 nmol/L; p < 0.0001), whereas their estimated daily calcium intake was higher (1.004 ± 0.23 vs 0.721 ± 0.25 g of controls; p = 0.0007). Age at menopause was significantly lower in nuns' group (p = 0.016). Incidence of fractures was higher in nuns (39% vs 10%; p = 0.0029), and the best predictors of fractures were age at menopause (odds ratio [OR]: 1.12; 95% confidence interval [CI]: 1.01-1.30), amplitude-dependent speed of sound T-score (OR: 1.15; 95% CI: 1.03-1.63), and bone transmission time T-score (OR: 1.30; 95% CI: 1.15-1.81). This study documented low 25-OH vit D levels, increased frequency of clinical fractures, and low bone mass detected by QUS in Southern Italian nuns.
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Absorciometria de Fóton/métodos , Densidade Óssea , Osteoporose Pós-Menopausa/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Vitamina D/análogos & derivados , Idoso , Índice de Massa Corporal , Feminino , Seguimentos , Humanos , Incidência , Itália/epidemiologia , Estilo de Vida , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/epidemiologia , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Vitamina D/sangueRESUMO
PURPOSE: To assess the pharmacokinetics, pharmacodynamics and tolerability of different doses of octreotide and pasireotide (subcutaneous [sc] and long-acting release [LAR]) when co-administered in healthy volunteers. METHODS: This was an exploratory, Phase I, single-centre study. Healthy adults were enrolled in a staggered approach into seven cohorts to receive octreotide and pasireotide (sc and LAR formulations), alone or in combination. Plasma drug concentrations, growth hormone (GH), insulin-like growth factor I (IGF-I), and plasma glucose were assessed at baseline, immediately after sc treatment, and 21 and 28 days after LAR treatment. RESULTS: Of 88 enrolled subjects, 52 and 82 participated in sc and LAR dosing phases, respectively. There were no relevant pharmacokinetic interactions between octreotide and pasireotide. In combination, pasireotide sc (150 µg) and octreotide sc (100/300 µg) resulted in numerically greater reductions in insulin levels and a higher incidence of AEs than either single agent; the rapid (within 1 h) increase in plasma glucose after pasireotide was delayed with combination treatment. Octreotide sc and pasireotide sc, alone or in combination, reduced IGF-I levels and led to undetectable GH levels in most subjects. During the LAR phase, addition of a low dose of pasireotide (5 mg) to a standard dose of octreotide (20 mg) resulted in an ~2-fold reduction in median IGF-I versus octreotide 20 mg 21 days post-dose; this effect was numerically greater than seen for pasireotide 20 mg alone. Peak plasma glucose was substantially lower after LAR than sc dosing. Interestingly, glucose levels were also numerically lower in the pasireotide 5 mg plus octreotide 20 mg group than for 20 mg of octreotide or pasireotide alone. AEs were less frequent after LAR than sc dosing. CONCLUSIONS: Combined low doses of pasireotide LAR (5 mg) and octreotide LAR (10-30 mg) provided greater suppression of IGF-I than either single agent and did not increase blood glucose or incidence of AEs versus either agent alone.
Assuntos
Acromegalia , Octreotida , Acromegalia/tratamento farmacológico , Adulto , Glicemia , Preparações de Ação Retardada/uso terapêutico , Hormônio do Crescimento , Voluntários Saudáveis , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Octreotida/efeitos adversos , Somatostatina/análogos & derivadosRESUMO
BACKGROUND: Adrenocortical carcinoma is a rare neoplasm characterized by a high risk of recurrence after radical resection. Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial. Our aim was to evaluate the efficacy of adjuvant mitotane in prolonging recurrence-free survival. METHODS: We performed a retrospective analysis involving 177 patients with adrenocortical cancer who had undergone radical surgery at 8 centers in Italy and 47 centers in Germany between 1985 and 2005. Adjuvant mitotane was administered to 47 Italian patients after radical surgery (mitotane group), whereas 55 Italian patients and 75 German patients (control groups 1 and 2, respectively) did not receive adjuvant treatment after surgery. RESULTS: Baseline features in the mitotane group and the control group from Italy were similar; the German patients were significantly older (P=0.03) and had more stage I or II adrenocortical carcinomas (P=0.02) than did patients in the mitotane group. Recurrence-free survival was significantly prolonged in the mitotane group, as compared with the two control groups (median recurrence-free survival, 42 months, as compared with 10 months in control group 1 and 25 months in control group 2). Hazard ratios for recurrence were 2.91 (95% confidence interval [CI], 1.77 to 4.78; P<0.001) and 1.97 (95% CI, 1.21 to 3.20; P=0.005), respectively. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival. Adverse events associated with mitotane were mainly of grade 1 or 2, but temporary dose reduction was needed in 13% of patients. CONCLUSIONS: Adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma.
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Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Mitotano/uso terapêutico , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/cirurgia , Antineoplásicos Hormonais/efeitos adversos , Quimioterapia Adjuvante , Humanos , Mitotano/efeitos adversos , Análise Multivariada , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Estudos Retrospectivos , Análise de SobrevidaRESUMO
OBJECTIVE: Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease. DESIGN: Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906). METHODS: Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. RESULTS: At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. CONCLUSION: mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
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Ritmo Circadiano , Hidrocortisona/metabolismo , Hipersecreção Hipofisária de ACTH/metabolismo , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/cirurgia , Adulto , Feminino , Hormônios/uso terapêutico , Humanos , Hidrocortisona/urina , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/etiologia , Hipersecreção Hipofisária de ACTH/urina , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Saliva/química , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11ß-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. METHODS: LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. FINDINGS: Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0-49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7-53·4]; p<0·0001). At week 24, 72 (53%; 95% CI 43·9-61·1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. INTERPRETATION: Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease. FUNDING: Novartis Pharma AG.
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Citocromo P-450 CYP11B2/antagonistas & inibidores , Imidazóis/administração & dosagem , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adulto , Citocromo P-450 CYP11B2/metabolismo , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/antagonistas & inibidores , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/metabolismo , Estudos Prospectivos , Resultado do TratamentoRESUMO
To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB (RANKL), and their relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor (n = 2) or beginning of therapy with phosphate and calcitriol when surgical treatment was impossible (n = 3). At diagnosis, TIO patients had higher levels of FGF-23 and bone-specific alkaline phosphatase (bALP) and lower levels of cathepsin K (CathK), RANKL, and RANKL/OPG ratio compared to controls. During the follow-up, FGF-23 decreased significantly only in patients who underwent a surgical excision, while phosphate and BMD increased in all patients. The increases in BMD, phosphate, and renal phosphate reabsorption rate were directly related. In the first 60 days of follow-up, we observed a prolonged inhibition of RANKL, CathK, and bone resorption markers associated with a persistence of TIO symptoms and an increase in bALP. From day 60, levels of bone turnover markers returned progressively within the normal range and a clinical remission was observed. The inhibition of the RANKL/OPG pathway and the uncoupling of bone formation and resorption observed in patients with active TIO may be a compensatory mechanism, attempting to reduce worsening of osteomalacia. The BMD increase during TIO treatment is related to the improvement of phosphate rather than FGF-23 levels. A "hungry bone"-like syndrome was observed after surgical or pharmacological treatment.
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Osso e Ossos/metabolismo , Neoplasias/complicações , Osteomalacia/etiologia , Osteomalacia/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Transdução de Sinais/fisiologia , Densidade Óssea/fisiologia , Reabsorção Óssea , Estudos de Casos e Controles , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Hemangiopericitoma/complicações , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , OsteogêneseRESUMO
PURPOSE: Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM. METHODS: Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0). RESULTS: Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders. CONCLUSION: Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS. GOV IDENTIFIER: NCT02299089.
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Acromegalia/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/farmacologia , Octreotida/farmacocinética , Acromegalia/complicações , Acromegalia/metabolismo , Acromegalia/patologia , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/farmacologia , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Octreotida/administração & dosagem , Prognóstico , Taxa de Sobrevida , Distribuição TecidualRESUMO
BACKGROUND: In patients with multiple endocrine neoplasia type 1 (MEN1), expression of somatostatin receptor (SST) in parathyroid adenomas and effectiveness of therapy with somatostatin analogues on primary hyperparathyroidism (PHP) have been scarcely investigated. OBJECTIVE: To evaluate the effects of depot long acting octreotide (OCT-LAR) in patients with MEN1-related PHP. PATIENTS: Eight patients with a genetically confirmed MEN1, presenting both PHP and duodeno-pancreatic neuroendocrine tumours (NET), were enrolled. DESIGN: The initial treatment was OCT-LAR 30 mg every 4 weeks. This therapy was established to stabilize the duodeno-pancreatic NET before to perform parathyroidectomy for PHP. Before OCT-LAR therapy, a SST scintigraphy was performed in all patients. SST subtype 2A immunohistochemistry was performed on parathyroid tumour samples from three patients undergone parathyroidectomy after OCT-LAR therapy. MEASUREMENTS: Serum concentrations of PTH, calcium and phosphorus as well as the 24-h urine calcium : creatinine ratio and the renal threshold phosphate concentration were evaluated before and after OCT-LAR. RESULTS: After OCT-LAR therapy, hypercalcaemia and hypercalciuria normalized in 75% and 62.5% of patients, respectively, and serum phosphorus and renal threshold phosphate significantly increased. Serum PTH concentrations significantly decreased in all patients and normalized in two of them. SST subtype 2A immunostaining was found in all parathyroid adenomas investigated, while SST scintigraphy showed a positive parathyroid tumour uptake in three of eight patients (37.5%). CONCLUSION: Six months of OCT-LAR therapy controlled hypercalcaemia and hypercalciuria in two-thirds of patients with MEN1-related PHP. Direct OCT-LAR effects mediated by binding to SST expression on parathyroid tumour cells are likely the main mechanism to explain the activity of this compound on calcium and phosphorus abnormalities in MEN1 PHP.
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Neoplasias Duodenais/tratamento farmacológico , Hiperparatireoidismo Primário/complicações , Neoplasia Endócrina Múltipla Tipo 1/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Octreotida/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacologia , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Humanos , Hiperparatireoidismo Primário/tratamento farmacológico , Hiperparatireoidismo Primário/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/complicações , Octreotida/farmacologia , Paratireoidectomia , Somatostatina/análogos & derivados , Adulto JovemRESUMO
BACKGROUND: Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. METHODS: In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1·5-5·0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1:1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to <2·0â×âULN and 2·0-5·0â×âULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1·5â×âULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0â×âULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. FINDINGS: Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41·9% [95% CI 30·5-53·9]) of 74 patients in the 10 mg group and 31 (40·8% [29·7-52·7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. INTERPRETATION: Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule. FUNDING: Novartis Pharma AG.
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Síndrome de Cushing/tratamento farmacológico , Hormônios/uso terapêutico , Somatostatina/análogos & derivados , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos , Segurança , Somatostatina/uso terapêutico , Resultado do TratamentoRESUMO
CONTEXT: Recently, great efforts have been made to understand the pathogenesis of bone loss after allogeneic stem cell transplant (allo-SCT) and possible treatments. EVIDENCE ACQUISITION: A literature search of the MEDLINE database was performed to find articles in English using the search terms "allogeneic stem cell transplant" or "bone marrow transplant," in combination with "bone loss," "osteoporosis treatment," "osteoblast," "cytokines," or "osteoprotegerin." Reference lists from the articles retrieved were also evaluated for relevant information. EVIDENCE SYNTHESIS: Bone mineral density at the lumbar spine, but not at the femur, can improve or even recover several years after SCT. Multiple risk factors for posttransplant bone loss have been recently identified: abnormalities in the immune system function and their treatments, reduced production of growth factors, osteoclast activation by increased cytokine release, and decreased number and function of osteoblast precursors within the stromal stem cell compartment. Pamidronate was partially successful in preventing posttransplant bone loss, whereas both oral and parenteral bisphosphonates had beneficial effects on documented osteoporosis in long-term survivors. CONCLUSIONS: There is clear evidence that transplant-related bone loss is a multifactorial, early, and possibly long-lasting disorder. All patients who have already received allo-SCT should be evaluated as to their bone status and treated with appropriate supportive measures and specific treatments as soon as abnormalities are detected. Although preventive antiresorptive treatments are only partially effective, they should be started in all patients before or at the time of allo-SCT, regardless of their bone mineral density values, and continued at least for the first year after transplant.
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Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/terapia , Transplante de Células-Tronco/efeitos adversos , Densidade Óssea , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , SobreviventesRESUMO
OBJECTIVE: Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Nevertheless, limited data are available on bone status in patients with endogenous cortisol excess. This study is aimed at investigating the role of sex steroids and severity of hypercortisolism on bone mineral density (BMD) and prevalence of vertebral fractures in female patients. DESIGN: Cross-sectional, case-control study. PATIENTS: Seventy-one consecutive women were enrolled: 36 with overt hypercortisolism (26 with ACTH-secreting pituitary adenoma and 10 with cortisol-secreting adrenal tumor) and 35 with subclinical hypercortisolism due to adrenal incidentalomas. They were compared with 71 matched controls. METHODS: At diagnosis, we measured serum cortisol, FSH, LH, estradiol, testosterone, androstenedione and DHEAS, and urinary cortisol excretion. BMD was determined by dual energy X-ray absorptiometry at the lumbar spine and femoral neck. Vertebral fractures were investigated by a semiquantitative scoring method. RESULTS: Between women with overt and subclinical hypercortisolism BMD values and prevalence of any vertebral (69 vs 57%, P = 0.56), clinical (28 vs 11.4%, P = 0.22), and multiple vertebral fractures (36 vs 31%, P = 0.92) did not differ. Among patients with subclinical hypercortisolism, amenorrhoic women had a lower BMD (P = 0.035) and more frequent vertebral fractures (80 vs 40%; P = 0.043) when compared with the eumenorrhoic ones. Among women with overt hypercortisolism, there was no difference in lumbar BMD (P = 0.37) and prevalence of fractures (81 vs 60%; P = 0.26) between those amenorrhoic and eumenorrhoic. By logistic regression analysis, lumbar spine BMD values and cortisol-to-DHEAS ratio were the best predictors of vertebral fractures (P < 0.01). CONCLUSIONS: Vertebral fractures are very common in women with endogenous cortisol excess, regardless of its severity. The deleterious effects of hypercortisolism on the spine may be partly counterbalanced by DHEAS increase at any degree of cortisol excess, and by preserved menstrual cycles in women with subclinical but not in those with overt hypercortisolism.
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Síndrome de Cushing/epidemiologia , Síndrome de Cushing/metabolismo , Hormônios Esteroides Gonadais/sangue , Osteoporose/epidemiologia , Osteoporose/metabolismo , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/metabolismo , Absorciometria de Fóton , Adulto , Idoso , Androstenodiona/sangue , Densidade Óssea , Estudos de Casos e Controles , Estudos Transversais , Sulfato de Desidroepiandrosterona/sangue , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hidrocortisona/sangue , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Índice de Gravidade de Doença , Fraturas da Coluna Vertebral/diagnóstico por imagem , Testosterona/sangueRESUMO
OBJECTIVE: The aim of this study was to evaluate the effects of estrogen-progestin therapy on serum levels of receptor-activating nuclear factor kappabeta ligand (RANKL), osteoprotegerin, osteocalcin, leptin, and ghrelin in a cross-sectional study of 99 healthy postmenopausal women conducted at the Menopause Clinic of our department. DESIGN: In this cross-sectional, observational study, 99 participants were divided into two groups. Group A was composed of 77 postmenopausal women who had never received estrogen-progestin therapy, and group B was composed of 22 postmenopausal women who had received transdermal 17beta-estradiol at a dose of 50 microg/day in a continuous regimen for at least 24 months and nomegestrol at a dose of 5 mg/day for 12 days/month in a sequential regimen. All participants underwent blood sampling in the morning and quantitative ultrasound bone-densitometry measurement of the proximal phalanges of the dominant hand. RESULTS: T score and amplitude-dependent speed of sound were significantly higher in group B than in group A. No significant differences in RANKL, osteoprotegerin, and osteocalcin were observed between the two groups. Serum leptin levels were significantly lower in group B than in group A, whereas ghrelin was significantly higher in group B than in group A. CONCLUSIONS: The data gathered in this preliminary study indicate that estrogen-progestin therapy may protect against postmenopausal bone loss, but this protective effect does not seem to be exerted through action on the RANK-RANKL-osteoprotegerin system. Similarly, although several reports suggest that leptin and ghrelin are involved in bone metabolism, we could not detect any important correlation of these two hormones with bone metabolism or bone status in treated and untreated postmenopausal women. Because of the limited number of treated participants and the study design, the results of this preliminary study must be confirmed in larger, prospective, longitudinal studies.
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Terapia de Reposição de Estrogênios , Estrogênios/uso terapêutico , Osteoprotegerina/sangue , Pós-Menopausa/efeitos dos fármacos , Progestinas/uso terapêutico , Ligante RANK/sangue , Administração Cutânea , Densidade Óssea/efeitos dos fármacos , Estudos Transversais , Feminino , Falanges dos Dedos da Mão/diagnóstico por imagem , Grelina , Humanos , Leptina/sangue , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose/prevenção & controle , Hormônios Peptídicos/sangue , Receptores para Leptina , UltrassonografiaRESUMO
Women undergoing stem cell transplantation (SCT) are mostly young and have more than 90% probability of ovarian failure, which is often permanent. A woman's age, use of radiotherapy and alkylating chemotherapy, and the allogeneic type of transplant are associated with a higher rate of premature ovarian failure and worse residual ovarian function. Premature ovarian failure has serious systemic and psychological effects that may need treatment and should be managed by practitioners trained to treat this particular population of women. Ultrasonographic evidence of ovarian follicles is often associated with a future resumption of cycles, but there are no serum markers to predict the return of ovarian function in these patients. In our center, the rate of ovarian function recovery was 7% after allogeneic SCT and 25% after autologous SCT (P<0.05). There are no guidelines on how to manage premature ovarian failure induced by myeloablative treatments followed by SCT. Because of the likelihood of the need for long-lasting estrogen plus progestin therapy (EPT) and the increased risk of secondary neoplasia after SCT, the EPT should be as physiological as possible. In our experience, the cyclical sequential combination of estradiol (2 mg daily) plus dydrogesterone (10 mg for 14 d/mo) was associated with excellent compliance because of its simple administration and few adverse effects. Such a treatment led to a dramatic improvement in vasomotor, urogenital, and psychological symptoms related to estrogen deficiency. However, in the allogeneic transplantation setting, up to 25% of women may suffer from gynecological chronic graft-versus-host disease, which may become apparent as hematocolpometra after introduction of EPT. Thus, accurate pretreatment evaluation and frequent monitoring during treatment are required. Moreover, EPT absorption may be reduced in patients who received allotransplants and have gastrointestinal or skin chronic graft-versus-host disease.
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Insuficiência Ovariana Primária/prevenção & controle , Transplante de Células-Tronco/efeitos adversos , Quimioterapia Combinada , Didrogesterona/administração & dosagem , Estradiol/administração & dosagem , Feminino , Humanos , Leucemia/terapia , Insuficiência Ovariana Primária/etiologiaRESUMO
Cushing's syndrome (CS) is a chronic and systemic disease caused by endogenous or exogenous hypercortisolism, associated with an increase of mortality rate due to the clinical consequences of glucocorticoid excess, especially cardiovascular diseases. After cure, usually obtained by the surgical removal of the tumor responsible for the disease, the normalization of cortisol secretion is not constantly followed by the recovery of the clinical complications developed during the active disease, and it is often followed by the development of novel clinical manifestations induced by the fall of cortisol levels. These evidences were mostly documented in patients with pituitary-dependent CS, after surgical resection of the pituitary tumor. Indeed, despite an improvement of the mortality rate, metabolic syndrome and the consequent cardiovascular risk have been found to partially persist after disease remission, strictly correlated to the insulin resistance. Skeletal diseases, mainly osteoporosis, improve after normalization of cortisol levels but require a long period of time or the use of specific treatment, mainly bisphosphonates, to reach the normalization of bone mass. A relevant improvement or resolution of mental disturbances has been described in patients cured from CS, although in several cases, cognitive decline persisted and psychological or psychiatric improvement was erratic, delayed, or incomplete. On the other hand, development or exacerbation of autoimmune disorders, mainly thyroid autoimmune diseases, was documented in predisposed patients with CS after disease remission. The totality of these complications persisting or occurring after successful treatment contribute to the impairment of quality of life registered in patients with CS after disease cure.
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Síndrome de Cushing , Doenças Autoimunes/etiologia , Doenças Ósseas/etiologia , Doenças Cardiovasculares/etiologia , Síndrome de Cushing/sangue , Síndrome de Cushing/complicações , Síndrome de Cushing/mortalidade , Síndrome de Cushing/cirurgia , Humanos , Hidrocortisona/sangue , Nefropatias/etiologia , Síndrome Metabólica/etiologia , Indução de Remissão , Resultado do TratamentoRESUMO
INTRODUCTION: The effects of endogenous cortisol (F) excess on bone mass and vertebral fractures have still not been thoroughly investigated. The aim of this cross-sectional case-control study was to investigate factors influencing bone demineralization and vertebral fractures in different conditions of F excess, i.e. Cushing's disease and adrenal and ectopic Cushing's syndrome. MATERIALS AND METHODS: Eighty consecutive patients and 80 controls were prospectively enrolled: 37 patients (21 females) with pituitary ACTH-secreting adenoma, 18 (14 females) with adrenocortical adenoma, 15 (11 females) with adrenal carcinoma of mixed secretion, and 10 (three females) with ectopic ACTH secretion. The groups had similar age. At diagnosis, bone mineral density (BMD) was determined by the dual-energy x-ray absorptiometry technique at the lumbar spine (L1-L4) and femoral neck; vertebral fractures were investigated by standard spinal radiographs. RESULTS: When comparing the groups with different etiology of F excess, the patients with ectopic ACTH secretion had higher F and lower BMD values than the other subgroups. Morning F (P = 0.03) and testosterone levels (P = 0.04) correlated with lumbar BMD. Vertebral fractures were found in 61 (76%) of the patients, were multiple in 52 (85%) of the cases, and clinically evident in 32 (52%). Only multiple fractures were more frequent in patients with ectopic ACTH hypersecretion (P < 0.05). Lumbar spine BMD was the best predictor of vertebral fractures (P < 0.01). Surprisingly, amenorrheic and eumenorrheic women had similar BMD values and fracture prevalence. CONCLUSION: A high prevalence (76%) of vertebral fracture was revealed, regardless of the etiology of the patients' hypercortisolism. The harmful effects of F excess at the spine were partly counterbalanced by the increased androgen production but were not affected by gonadal status in women.
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Desmineralização Patológica Óssea/etiologia , Hidrocortisona/sangue , Ovário/fisiopatologia , Fraturas da Coluna Vertebral/etiologia , Testículo/fisiopatologia , Adenoma/sangue , Adolescente , Neoplasias das Glândulas Suprarrenais/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Biomarcadores , Índice de Massa Corporal , Carcinoma/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
CONTEXT: Polycystic ovary syndrome (PCOS) is associated with early impairment of vascular structure and a low-grade chronic inflammation. Aldosterone is a well-recognized cardiovascular risk (CVR) factor and is related to inflammatory processes. OBJECTIVE: Our objective was to investigate serum aldosterone levels in PCOS and correlate them to some CVR factors and early atherosclerotic markers. DESIGN AND SETTING: A prospective baseline-controlled clinical study was conducted at the University "Federico II" of Naples School of Medicine (Naples, Italy). PATIENTS: Fifty PCOS women age- and body mass index-matched with 50 healthy women were enrolled. MEAN OUTCOME MEASURES: Anthropometric, hormonal, and metabolic patterns, including plasma aldosterone, renin, and C-reactive protein, were measured in each subject. Intima-media thickness was also evaluated in each patient and control. RESULTS: Aldosterone levels were significantly increased (P < 0.001) in PCOS compared with healthy women (10.5 +/- 3.2 vs. 5.7 +/- 2.5 ng/dl). In PCOS, a significant (P < 0.001) direct correlation between plasma aldosterone and homeostasis model assessment, C-reactive protein, intima-media thickness, and mean blood pressure was found. On the other hand, high-density lipoprotein cholesterol and potassium were inversely (P < 0.001) related to serum aldosterone. Multiple linear regression analysis showed that the area under the curve for insulin and homeostasis model assessment was linearly related to aldosterone in PCOS. CONCLUSION: PCOS women show an insulin resistance related increase in serum aldosterone levels.