Search Results
You are looking at 71 - 78 of 78 items for
- Abstract: Birth defect x
- Abstract: Bisphenol-A x
- Abstract: Drugs x
Search for other papers by Nelma Veronica Marques in
Google Scholar
PubMed
Search for other papers by Luiz Eduardo Armondi Wildemberg in
Google Scholar
PubMed
Search for other papers by Monica R Gadelha in
Google Scholar
PubMed
Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor 1 (IGF1) levels to below the upper limit of the normal range, with some patients responding within 1−3 months of treatment (n = 11) and others after ≥4 months (n = 9). Following pasireotide dose reduction, IGF1 levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.
Significance statement
Patients with acromegaly often need medical therapy for extended periods of time, and pasireotide is an effective, long-term treatment option. However, pasireotide may increase blood glucose levels in some patients, such as those with pre-existing diabetes. In this single-centre study, we show that following dose reduction of pasireotide over time, patients with acromegaly maintained their biochemical response (IGF1 < ULN) and had improved glycaemic control. As such, dose reductions may be an effective, personalised treatment approach for managing some patients receiving long-term pasireotide therapy and could allow patients to achieve early and long-term biochemical control while minimising adverse drug effects.
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Search for other papers by Angelica Sharma in
Google Scholar
PubMed
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Search for other papers by Katharine Lazarus in
Google Scholar
PubMed
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Search for other papers by Deborah Papadopoulou in
Google Scholar
PubMed
Search for other papers by Hemanth Prabhudev in
Google Scholar
PubMed
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Department of Clinical Biochemistry, North West London Pathology, London, UK
Search for other papers by Tricia Tan in
Google Scholar
PubMed
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Search for other papers by Karim Meeran in
Google Scholar
PubMed
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Department of Clinical Biochemistry, North West London Pathology, London, UK
Search for other papers by Sirazum Choudhury in
Google Scholar
PubMed
Context
Patients with adrenal insufficiency (AI) have a higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice- or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance through its convenience.
Objectives
Prednisolone day curves can be used to accurately downtitrate patients to the minimum effective dose. This study aimed to review prednisolone day curves and determine therapeutic ranges at different time points after administration.
Methods
Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Spearman’s correlation coefficient was used to determine the relationship between 2-, 4-, and 6-h prednisolone levels compared to the previously validated standard 8-h prednisolone level (15–25 μg/L).
Results
The median dose was 4 mg of prednisolone once daily. There was a strong correlation between the 4- and 8-h (R = 0.8829, P ≤ 0.0001) and 6- and 8-h prednisolone levels (R = 0.9530, P ≤ 0.0001). Target ranges for prednisolone were 37–62 μg/L at 4 h, 24–39 μg/L at 6 h, and 15–25 μg/L at 8 h. Prednisolone doses were successfully reduced in 21 individuals, and of these, 3 were reduced to 2 mg once daily. All patients were well upon follow-up.
Conclusion
This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low-dose prednisolone of 2–4 mg is safe and effective in most patients with AI. Doses can be titrated with either 4-, 6-, or 8-h single time point drug levels.
Search for other papers by Zhengrong Jiang in
Google Scholar
PubMed
Search for other papers by Linghong Huang in
Google Scholar
PubMed
Search for other papers by Lijun Chen in
Google Scholar
PubMed
Search for other papers by Jingxiong Zhou in
Google Scholar
PubMed
Search for other papers by Bo Liang in
Google Scholar
PubMed
Search for other papers by Xuefeng Bai in
Google Scholar
PubMed
Search for other papers by Lizhen Wu in
Google Scholar
PubMed
Search for other papers by Huibin Huang in
Google Scholar
PubMed
Background
Graves’ disease is a common autoimmune disease. Cytokines and their signalling pathways play a major part in the pathogenesis of Graves’ disease; however, the underlying mechanism needs to be clarified.
Aims
The aim of this study was to explore whether circular RNAs participate in the immunological pathology of Graves’ disease via cytokine-related signalling pathways.
Methods
Bioinformatics analysis was performed to identify differentially expressed circular RNAs and their targets and associated pathways. A total of three patients with Graves’ disease and three sex- and age-matched healthy controls were enrolled for validation with microarray analysis and real-time quantitative PCR (qPCR). An additional 24 patients with Graves’ disease and 24 gender- and age-matched controls were included for validation by real-time fluorescent qPCR. Flow cytometry and CCK8 assays were used to detect the apoptotic and proliferative levels of Jurkat cells (T lymphocytes) with the silenced expression of circRNA. ELISA was performed to detect the growth and apoptosis-related proteins. The competition mechanism of endogenous RNA was explored by real-time fluorescence qPCR.
Results
A total of 366 significantly differentially expressed circular RNAs were identified in the Graves’ disease group compared to healthy controls. The level of hsa_circ_0090364 was elevated in Graves’ disease patients and positively correlated with thyroid-stimulating hormone receptor antibodies. Further analyses suggested that hsa_circ_0090364 may regulate the JAK-STAT pathway via the hsa-miR-378a-3p/IL-6ST/IL21R axis to promote cell growth.
Conclusions
These results provide novel clues into the pathophysiological mechanisms of Graves’ disease and potential targets for drug treatment.
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, INSERM, UMRS1138, Paris, France
Search for other papers by Jean-Philippe Bertocchio in
Google Scholar
PubMed
Search for other papers by Natalie Grosset in
Google Scholar
PubMed
Search for other papers by Lionel Groussin in
Google Scholar
PubMed
Search for other papers by Peter Kamenický in
Google Scholar
PubMed
Search for other papers by Fabrice Larceneux in
Google Scholar
PubMed
Search for other papers by Anne Lienhardt-Roussie in
Google Scholar
PubMed
Université Paris-Saclay, Inserm U1185, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et Diabète de l’Enfant, Centre de Référence des Maladies Rares du Calcium et du Phosphore et Filière de Santé Maladies Rares OSCAR, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France
Search for other papers by Agnès Linglart in
Google Scholar
PubMed
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Assistance Publique-Hôpitaux de Paris, Institut Necker-Enfants Malades, INSERM U1151 – CNRS UMR 8253, Paris, France
Search for other papers by Gérard Maruani in
Google Scholar
PubMed
Association Francophone de Chirurgie Endocrinienne (AFCE), France
Search for other papers by Eric Mirallie in
Google Scholar
PubMed
Search for other papers by François Pattou in
Google Scholar
PubMed
Search for other papers by Riyad N H Seervai in
Google Scholar
PubMed
Search for other papers by Coralie Sido in
Google Scholar
PubMed
Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Biochimie et Génétique Moléculaires, Paris, France
INSERM, U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France
Search for other papers by Caroline Silve in
Google Scholar
PubMed
INSERM, U1418, CIC-EC, Hôpital Européen Georges Pompidou, Paris, France
Search for other papers by Aurélie Vilfaillot in
Google Scholar
PubMed
Search for other papers by Antoine Tabarin in
Google Scholar
PubMed
Search for other papers by Marie-Christine Vantyghem in
Google Scholar
PubMed
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, INSERM, UMRS1138, Paris, France
CNRS, ERL8228, Paris, France
Search for other papers by Pascal Houillier in
Google Scholar
PubMed
Search for other papers by the investigators of the Épi-Hypo study in
Google Scholar
PubMed
Context
Recent guidelines have provided recommendations for the care of patients with chronic hypoparathyroidism. Very little is known about actual physicians’ practices or their adherence to such guidelines.
Objective
To describe the physicians’ practice patterns and their compliance with international guidelines.
Design
The cohort studies included were Épi-Hypo (118 physicians and 107 patients, from September 2016 to December 2019) and ePatients (110 patients, November 2019).
Methods
Internet-based cohorts involving all settings at a nationwide level (France). Participants were (i) physicians treating patients with chronic hypoparathyroidism and patients with chronic hypoparathyroidism either participating in the (ii) Épi-Hypo study (Épi-Hypo 2019 patients), or (iii) Hypoparathyroidism France, the national representative association (ePatients).
Results
The physicians’ specialties were mainly endocrinology (61%), nephrology (28%), family medicine (2.5%), pediatrics (2.5%), rheumatology (2%), or miscellaneous (4%) and 45% were practicing in public universities. The median number of pharmaceutical drug classes prescribed was three per patient. The combination of active vitamin D and calcium salt was given to 59 and 58% of ePatients and Épi-Hypo 2019 patients, respectively. Eighty-five percent of ePatients and 87% of physicians reported monitoring plasma calcium concentrations at a steady state at least twice a year. In 32 and 26% of cases, respectively, ePatients and physicians reported being fully in accordance with international guidelines that recommend targeting symptoms, plasma calcium and phosphate values, and urine calcium excretion.
Conclusions
The care of patients with chronic hypoparathyroidism involves physicians with very different practices, so guidelines should include and target other specialists as well as endocrinologists. Full adherence to the guidelines is low in France.
Search for other papers by Rachel Forfar in
Google Scholar
PubMed
Search for other papers by Mashal Hussain in
Google Scholar
PubMed
Search for other papers by Puneet Khurana in
Google Scholar
PubMed
Search for other papers by Jennifer Cook in
Google Scholar
PubMed
Search for other papers by Steve Lewis in
Google Scholar
PubMed
Search for other papers by Dillon Popat in
Google Scholar
PubMed
Search for other papers by David Jackson in
Google Scholar
PubMed
Search for other papers by Ed McIver in
Google Scholar
PubMed
Search for other papers by Jeff Jerman in
Google Scholar
PubMed
Search for other papers by Debra Taylor in
Google Scholar
PubMed
Search for other papers by Adrian JL Clark in
Google Scholar
PubMed
Search for other papers by Li F Chan in
Google Scholar
PubMed
The overproduction of adrenocorticotropic hormone (ACTH), in conditions such as Cushing’s disease and congenital adrenal hyperplasia (CAH), leads to significant morbidity. Current treatment with glucocorticoids does not adequately suppress plasma ACTH, resulting in excess adrenal androgen production. At present, there is no effective medical treatment in clinical use that would directly block the action of ACTH. Such a therapy would be of great clinical value. ACTH acts via a highly selective receptor, the melanocortin-2 receptor (MC2R) associated with its accessory protein MRAP. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and the high degree of ligand specificity suggest that antagonism of this receptor could provide a useful therapeutic strategy in the treatment of conditions of ACTH excess. To this end, we screened an extensive library of low-molecular-weight drug-like compounds for MC2R antagonist activity using a high-throughput homogeneous time-resolved fluorescence cAMP assay in Chinese hamster ovary cells stably co-expressing human MC2R and MRAP. Hits that demonstrated MC2R antagonist properties were counter-screened against the β2 adrenergic receptor and dose–response analysis undertaken. This led to the identification of a highly specific MC2R antagonist capable of antagonising ACTH-induced progesterone release in murine Y-1 adrenal cells and having selectivity for MC2R amongst the human melanocortin receptors. This work provides a foundation for the clinical investigation of small-molecule ACTH antagonists as therapeutic agents and proof of concept for the screening and discovery of such compounds.
Search for other papers by Emily Warmington in
Google Scholar
PubMed
Search for other papers by Gabrielle Smith in
Google Scholar
PubMed
Search for other papers by Vasileios Chortis in
Google Scholar
PubMed
Department of Neurosurgery, Technical University Munich (TMU), Munich, Germany
Search for other papers by Raimunde Liang in
Google Scholar
PubMed
Search for other papers by Juliane Lippert in
Google Scholar
PubMed
Search for other papers by Sonja Steinhauer in
Google Scholar
PubMed
Search for other papers by Laura-Sophie Landwehr in
Google Scholar
PubMed
Medizinische Klinik Und Poliklinik III, University Hospital Carl Gustav Carus, Dresden, Germany
Search for other papers by Constanze Hantel in
Google Scholar
PubMed
Search for other papers by Katja Kiseljak-Vassiliades in
Google Scholar
PubMed
Search for other papers by Margaret E Wierman in
Google Scholar
PubMed
Search for other papers by Barbara Altieri in
Google Scholar
PubMed
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Search for other papers by Paul A Foster in
Google Scholar
PubMed
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Search for other papers by Cristina L Ronchi in
Google Scholar
PubMed
Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.
Search for other papers by Caiyan Mo in
Google Scholar
PubMed
Search for other papers by Tao Tong in
Google Scholar
PubMed
Search for other papers by Ying Guo in
Google Scholar
PubMed
Search for other papers by Zheng Li in
Google Scholar
PubMed
Search for other papers by Liyong Zhong in
Google Scholar
PubMed
Purpose
The coexistence of growth hormone-secreting pituitary adenoma (GHPA) and Graves' disease (GD) is rare. This study aimed to investigate the relationship between growth hormone (GH)/insulin-like growth factor 1 (IGF-1) levels and thyroid function in patients with GHPA combined with GD and to explore the underlying mechanisms.
Methods
Eleven patients with GHPA combined with GD during 2015-2022 were collected by searching the medical record system of Beijing Tiantan Hospital, Capital Medical University. Changes in GH/IGF-1 levels and thyroid function were compared before and after the application of antithyroid drugs (ATD) and before and after transsphenoidal surgery (TSS) or somatostatin analog (SSA) treatment, respectively.
Results
After the application of ATD, with the decrease of thyroid hormone levels, GH/IGF-1 levels also decreased gradually. In patients without ATD application, after surgery or SSA treatment, thyroid hormone levels decreased as GH/IGF-1 decreased.
Conclusion
Hyperthyroidism due to GD promotes the secretion of GH/IGF-1, and when thyroid hormone levels were decreased by the use of ATD, GH and IGF-1 levels were also decreased, suggesting that thyroid hormones may influence the synthesis and secretion of GH/IGF-1. The use of ATD to control thyrotoxicosis before TSS is not only beneficial in reducing the risk of anesthesia but may help to promote biochemical control of GHPA. On the other hand, high levels of GH/IGF-1 in patients with GHPA also exacerbate GD hyperthyroidism, which is ameliorated by a decrease in GH/IGF-1 levels by TSS or SSA treatment, suggesting that the GH–IGF-1 axis promotes growth, thyroid function, and thyroid hormone metabolism.
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Search for other papers by Lisa Arnetz in
Google Scholar
PubMed
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Search for other papers by Neda Rajamand Ekberg in
Google Scholar
PubMed
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Search for other papers by Kerstin Brismar in
Google Scholar
PubMed
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Search for other papers by Michael Alvarsson in
Google Scholar
PubMed
Objective
Dysfunction of the hypothalamus–pituitary–adrenal (HPA) axis has been implicated in type 2 diabetes (T2D). The aim of this study was to investigate the impact of T2D and gender on the HPA axis.
Methods
Synthetic ACTH (1 μg) was administered to 21 subjects with T2D (age 62 (54–70) years, 11 men/ten women, HbA1c 49±2 mmol/mol, treated with diet or oral antidiabetic drugs) and 38 controls (age 58 (41–67) years, 20 men/18 women). Fasting basal B-glucose, serum cortisol, insulin, IGF1 and IGFBP1 concentrations were measured, and sampling for all but IGF1 was repeated 30, 60, and 90 min after ACTH injection. Patients took 0.25 mg dexamethasone at 2200–2300 h and returned the next morning for the measurement of serum cortisol concentration.
Design
Cross-sectional study.
Results
Patients with T2D had similar fasting serum cortisol, IGF1 and IGFBP1 concentrations; however, serum cortisol concentration after administration of dexamethasone did not differ between the groups. Healthy women exhibited higher peak cortisol levels compared with healthy men (675±26 vs 582±21 nmol/l, P=0.014), while the peak levels were equally high in men and women with T2D, resulting in a higher peak level in men with T2D compared with healthy men (691±42 vs 582±21 nmol/l, P=0.024). Serum cortisol concentration after administration of dexamethasone did not differ between the groups, nor did IGF1 and IGFBP1.
Novelty of the findings
Some studies have previously indicated disturbed regulation of the hypothalamus–pituitary–adrenal (HPA) axis in subjects with type 2 diabetes (T2D); however, much remains unknown in this area. To the best of our knowledge, this is the first study to show that the gender difference in the adrenal response to ACTH (with greater reactivity in women) is abolished in T2D. While the clinical implications cannot be determined by this paper, it is known that gender differences exist in the pathogenesis and complications of T2D. Thus, our findings suggest that further research into gender differences in the HPA axis is warranted.
Conclusions
Gender differences in adrenal response to ACTH were abolished in T2D. Men with T2D had a higher peak cortisol compared with controls. Further studies are needed to elucidate the clinical implications.