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International Journal of Molecular... Jan 2023Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal... (Review)
Review
Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation.
Topics: Female; Humans; Prader-Willi Syndrome; Transcranial Direct Current Stimulation; Hyperphagia; Anxiety; Mothers
PubMed: 36768472
DOI: 10.3390/ijms24032150 -
Hormone Research in Paediatrics Jul 2023Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and...
Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in 'developed' countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.
PubMed: 37454648
DOI: 10.1159/000531766 -
Healthcare (Basel, Switzerland) Feb 2022Hypertension in pregnancy causes significant maternal and fetal mortality and morbidity. A comprehensive assessment of the effectiveness of antihypertensive drugs for... (Review)
Review
BACKGROUND
Hypertension in pregnancy causes significant maternal and fetal mortality and morbidity. A comprehensive assessment of the effectiveness of antihypertensive drugs for severe hypertension during pregnancy is needed to make informed decisions in clinical practice. This systematic review aimed to assess the efficacy and safety of antihypertensive drugs in severe hypertension during pregnancy.
METHODS
A systematic review using the electronic databases MEDLINE (PubMed) and Cochrane Library was performed until August 2021. The risk-of-bias 2 tool was used to assess the risk-of-bias in each study included. Meta-analysis was conducted to assess heterogeneity and to estimate the pooled effects size.
RESULTS
Seventeen studies fulfilled the inclusion criteria and 11 were included in the meta-analysis. Nifedipine was estimated to have a low risk in persistent hypertension compared to hydralazine (RR 0.40, 95% CI 0.23-0.71) and labetalol (RR 0.71, 95% CI 0.52-0.97). Dihydralazine was associated with a lower risk of persistent hypertension than ketanserin (RR 5.26, 95% CI 2.01-13.76). No difference was found in the risk of maternal hypotension, maternal and fetal outcomes, and adverse effects between antihypertensive drugs, except for dihydralazine, which was associated with more adverse effects than ketanserin.
CONCLUSIONS
Several drugs can be used to treat severe hypertension in pregnancy, including oral/sublingual nifedipine, IV/oral labetalol, oral methyldopa, IV hydralazine, IV dihydralazine, IV ketanserin, IV nicardipine, IV urapidil, and IV diazoxide. In addition, nifedipine may be preferred as the first-line agent. There was no difference in the risk of maternal hypotension, maternal and fetal outcomes, and adverse effects between the drugs, except for adverse effects in IV dihydralazine and IV ketanserin.
PubMed: 35206939
DOI: 10.3390/healthcare10020325 -
Diabetes, Metabolic Syndrome and... 2020Insulin autoimmune syndrome (IAS), also named Hirata's disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin... (Review)
Review
Insulin autoimmune syndrome (IAS), also named Hirata's disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies (IAA). IAS is a form of immune-mediated hypoglycemia, which develops when a triggering factor (ie, a medication or a viral infection) acts on an underlying predisposing genetic background. IAS pathogenesis involves the formation of insulin-IAA complexes that induce glycemic alterations with a double-phase mechanism: IAA prevent insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. The gold standard for the definitive diagnosis is the finding of IAA in a blood sample. Because IAS is frequently a self-remitting disease, its management mostly consists of supportive measures, such as dietary modifications, aimed at preventing the development of hypoglycemia. Pharmacological therapies may occasionally be necessary for patients presenting with severe manifestations of IAS. Available therapies may include drugs that reduce pancreatic insulin secretion (somatostatin analogues and diazoxide, for instance) and immunosuppressive agents (glucocorticoids, azathioprine and rituximab). The purpose of this review is to provide a comprehensive analysis of the disease, by describing the burden of knowledge that has been obtained in the 50 years following its first description, took in 1970, and by highlighting the points that are still unclear in its pathogenesis and management.
PubMed: 32308449
DOI: 10.2147/DMSO.S219438 -
Expert Opinion on Pharmacotherapy Apr 2021: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult...
: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult because the pharmacological-armamentarium available was limited. Recently, new therapeutic strategies have increased but it also generated controversies/uncertainties.: The authors briefly review: established/proposed F-NENs; the rationale for treatments; the recommended initial-pharmacotherapeutic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN. Also discussed are controversies/uncertainties related to new treatments.: Unfortunately, except for patients with insulinomas (>90-95%), gastrinomas (<20-40%), a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas, gastrinomas, and ACTHomas, long-acting somatostatin-analogs are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignancy, diazoxide is the initial drug-treatment; for gastrinomas, oral PPIs; and for ACTHomas, steroidogenesis inhibitors. There are now several secondary pharmacotherapeutic treatments. Surgery and liver-directed therapies also have a role in selected patients. Particularly promising is the recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin
PubMed: 33131345
DOI: 10.1080/14656566.2020.1845651 -
The Lancet. Diabetes & Endocrinology Dec 2022Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period.
BACKGROUND
Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.
METHODS
This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522.
FINDINGS
Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.
INTERPRETATION
Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.
FUNDING
Rhythm Pharmaceuticals.
Topics: Humans; Receptor, Melanocortin, Type 4; Alstrom Syndrome; Bardet-Biedl Syndrome; Treatment Outcome; Obesity
PubMed: 36356613
DOI: 10.1016/S2213-8587(22)00277-7 -
The Journal of Clinical Endocrinology... Jun 2023Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region,... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.
OBJECTIVE
The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones.
METHODS
In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo.
RESULTS
DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).
CONCLUSION
DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.
Topics: Humans; Prader-Willi Syndrome; Diazoxide; COVID-19; Obesity; Hyperphagia
PubMed: 36639249
DOI: 10.1210/clinem/dgad014 -
Hormone Research in Paediatrics 2022Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the... (Review)
Review
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the field has advanced significantly. It was the development of the insulin radioimmunoassay by Yalow and Berson a decade later that made it possible to demonstrate that this form of persistent hypoglycemia was caused by insulin, and a few years later, Drash described the successful treatment of children with hyperinsulinism with the antihypertensive diazoxide, which until today remains the only approved treatment for hyperinsulinism. In the mid 1970s, Baker and Stanley described that hyperinsulinism can be recognized by inappropriate responses of metabolic fuels and hormones during the course of a provocative fasting challenge. Later, advances in molecular genetics led to the discovery of the different genetic subtypes of hyperinsulinism. One of the most impactful discoveries in the field was the recognition of the focal form of hyperinsulinism and the development of 18F-DOPA PET for the localization of focal lesions before surgery which has resulted in the possibility of cure for children with focal disease. However, treatment options for children with nonfocal diazoxide-unresponsive hyperinsulinism have continued to be limited. New drug development programs for hyperinsulinism promise to change this in the next few years. Unfortunately, despite all these advances, children with hyperinsulinism around the world continue to experience neurological sequelae at high rates, highlighting the importance of early diagnosis and effective treatment.
Topics: Child; Humans; Infant; Infant, Newborn; Antihypertensive Agents; Congenital Hyperinsulinism; Diazoxide; Insulin
PubMed: 36446321
DOI: 10.1159/000526442