RESUMO
OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.
Assuntos
Síndrome de Cushing , Síndrome do QT Longo , Humanos , Estudos Cross-Over , Síndrome de Cushing/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Voluntários Saudáveis , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológico , Moxifloxacina , Receptores de Glucocorticoides , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
Maternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy.
RESUMO
PURPOSE: Craniopharyngiomas are nonmalignant sellar and parasellar tumors exhibiting a bimodal age distribution. While the outcomes following treatment in patients with childhood-onset craniopharyngiomas are well characterized, similar information in adult-onset craniopharyngiomas is limited. We aimed to describe the long-term outcomes (weight and metabolic parameters, mortality) in patients with adult-onset craniopharyngioma following treatment. METHODS: Patients with adult-onset craniopharyngioma with initial treatment (1993-2017) and >6 months of follow-up at our institution were retrospectively identified. Body mass index (BMI) categories included obese (BMI ≥ 30 kg/m2), overweight (BMI 25-29.9 kg/m2), and normal weight (BMI < 25 kg/m2). RESULTS: For the 91 patients with adult-onset craniopharyngioma (44% women, mean diagnosis age 48.2 ± 18 years) over a mean follow-up of 100.3 ± 69.5 months, weight at last follow-up was significantly higher than before surgery (mean difference 9.5 ± 14.8 kg, P < 0.001) with a higher percentage increase in weight seen in those with lower preoperative BMI (normal weight (20.7 ± 18%) vs. overweight (13.3 ± 18.0%) vs. obese (6.4 ± 15%), P = 0.012). At last follow-up, the prevalence of obesity (62 vs. 40.5%, P = 0.0042) and impaired glucose metabolism (17.4% vs. 34%, P = 0.017) increased significantly. All-cause mortality was 12%, with the average age of death 71.9 ± 19.7 years (average U.S. life expectancy 77.7 years, CDC 2020). CONCLUSION: Patients with adult-onset craniopharyngioma following treatment may experience weight gain, increased prevalence of obesity, impaired glucose metabolism, and early mortality. Lower preoperative BMI is associated with a greater percentage increase in postoperative weight.
Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Criança , Craniofaringioma/complicações , Craniofaringioma/epidemiologia , Craniofaringioma/cirurgia , Feminino , Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia , Sobrepeso/complicações , Sobrepeso/epidemiologia , Neoplasias Hipofisárias/cirurgia , Estudos RetrospectivosRESUMO
Establishing a definitive diagnosis of Cushing disease (CD), given its clinical and biochemical heterogeneity, initiating effective treatment to control the effects of hypercortisolism, and managing recurrence are challenging disease aspects to address. Mifepristone is a competitive glucocorticoid receptor antagonist that is approved in the US by the Food and Drug Administration to control hyperglycemia secondary to endogenous hypercortisolism (Cushing syndrome) in patients who have glucose intolerance or type 2 diabetes mellitus and have failed surgery or are not candidates for surgery. Herein, we describe 6 patients with CD who received mifepristone as adjunct/bridge therapy in the following clinical settings: to assess clinical benefits of treatment for suspected recurrent disease, to control hypercortisolism preoperatively for severe disease, to control hypercortisolism during the COVID-19 pandemic, and to provide adjunctive treatment to radiation therapy. The patients were treated at multiple medical practice settings. Mifepristone treatment in each of the described cases was associated with clinical improvements, including improvements in overall glycemia, hypertension, and weight loss. In addition, in one case where biochemical and radiological evidence of disease recurrence was uncertain, clinical improvement with mifepristone pointed toward likely disease recurrence. Adverse events associated with mifepristone reported in the 6 cases were consistent with those previously reported in the pivotal trial and included cortisol withdrawal symptoms, antiprogesterone effects (vaginal bleeding), hypothyroidism (treated with levothyroxine), and hypokalemia (treated with spironolactone). These cases show how mifepristone can potentially be utilized as a therapeutic trial in equivocal cases of CD recurrence; as a presurgical treatment strategy, particularly during the COVID-19 pandemic; and as bridge therapy, while awaiting the effects of radiation.
RESUMO
CONTEXT: Chronic opioid use may lead to adrenal insufficiency because of central suppression of the hypothalamic-pituitary-adrenal axis. However, the prevalence of opioid-induced adrenal insufficiency (OIAI) is unclear. OBJECTIVE: To determine the prevalence of OIAI and to identify predictors for the development of OIAI in patients taking opioids for chronic pain. DESIGN: Cross-sectional study, 2016-2018. SETTING: Referral center. PATIENTS: Adult patients taking chronic opioids admitted to the Pain Rehabilitation Center. MAIN OUTCOME MEASURE: Diagnosis of OIAI was considered if positive case detection (cortisolâ
<â
10 mcg/dL, ACTHâ
<â
15 pg/mL, and dehydroepiandrosterone sulfateâ
<â
25 mcg/dL), and confirmed after endocrine evaluation. Daily morphine milligram equivalent (MME) was calculated. RESULTS: In 102 patients (median age, 53 years [range, 22-83], 67% women), median daily MME was 60 mg (3-840), and median opioid therapy duration was 60 months (3-360). Abnormal case detection testing was found in 11 (10.8%) patients, and diagnosis of OIAI was made in 9 (9%). Patients with OIAI were on a higher daily MME (median, 140 [20-392] mg vs 57 [3-840] mg, Pâ
=â
0.1), and demonstrated a 4 times higher cumulative opioid exposure (median of 13,440 vs 3120 mg*months, Pâ
=â
0.03). No patient taking