Gender-Related Differences in the Presentation and Course of Cushing's Disease

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Effect of retinoic acid on human adrenal corticosteroid synthesis.

AbstractAimsRetinoic acid has recently yielded promising results in the treatment of Cushing's disease, i.e., excess cortisol secretion due to a pituitary corticotropin (ACTH)-secreting adenoma. In addition to its effect on the tumoral corticotrope cell, clinical results suggest an additional adrenal site of action. Aim of this study was to evaluate whether retinoic acid modulates cortisol synthesis and secretion by human adrenals in vitro.Main methodsPrimary cultures from 10 human adrenals specimens were incubated with 10nM, 100nM and 1μM retinoic acid with and without 10nM ACTH for 24h. Cortisol levels were measured by radioimmunoassay and CYP11A1, STAR and MC2R gene expression analyzed by real-time PCR.Key findingsRetinoic acid increased cortisol secretion (149.5±33.01%, 151.3±49.45% and 129.3±8.32% control secretion for 10nM, 100nM and 1μM respectively, p<0.05) and potentiated STAR expression (1.51±0.22, 1.56±0.15 and 1.59±0.14 fold change over baseline, for 10nM, 100nM and 1μM respectively, p<0.05). Concurrently, retinoic acid markedly blunted constitutional and ACTH-induced MC2R expression (0.66±0.11, 0.62±0.08 and 0.53±0.07 fold change over baseline, for 10nM, 100nM and 1μM respectively, p<0.05; 0.71±0.10, 0.51±0.07 and 0.51±0.08 fold change over ACTH alone, for 10nM, 100nM and 1μM respectively, p<0.05). No effect on CYP11A1 was observed.SignificanceRetinoic acid stimulates cortisol synthesis and secretion in human adrenals and at the same time markedly blunts ACTH receptor transcription. These results reveal a novel, adrenal effect of retinoic acid which may contribute to its efficacy in patients with Cushing's disease

No Untoward Effect of Long-Term Ketoconazole Administration on Electrocardiographic QT Interval in Patients with Cushing's Disease.

Ketoconazole is listed among drugs that prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, for example hypokalaemia and left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects their QT interval. The aim of this study was to assess the QT interval in patients with Cushing's disease during long-term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age: 37.8 ± 2.66 years) on ketoconazole treatment (100 mg-800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2 ± 7.17 versus 403.3 ± 6.05 msec. in women; 424.3 ± 23.54 versus 398.0 ± 14.93 msec. in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT-prolonging drugs. In conclusion, long-term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations drawn for other low-risk QT-prolonging drugs with attention to specific risk factors, for example hypokalaemia and drug interactions

グリコシド結合形成反応を中心とした糖質化合物の化学変換

博士（理学）神戸大

Effects of somatostatin analogues on muscle sympathetic nerve activity in acromegaly

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Efficacy and safety of once-monthly pasireotide in Cushing's disease: A 12 month clinical trial

© 2017 Elsevier Ltd. 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 < 2·0 × ULN and 2·0-5·0 × ULN). 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 1·5 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × ULN. 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