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International Journal of Endocrinology 2020Congenital hyperinsulinism (CHI) is a rare and life-threatening genetic disorder. Sirolimus as a mammalian target of rapamycin inhibitor may be helpful in patients with...
BACKGROUND
Congenital hyperinsulinism (CHI) is a rare and life-threatening genetic disorder. Sirolimus as a mammalian target of rapamycin inhibitor may be helpful in patients with CHI who do not respond well to other treatments including diazoxide and octreotide. However, the safety and efficacy of this therapy are still unclear. This study aimed to evaluate the potential therapeutic effects of sirolimus in CHI patients with mutations in the ABCC8 and KCNJ11 genes.
METHODS
During the period of this follow-up study, every child with a confirmed diagnosis of unresponsive CHI underwent genetic evaluation. Among those who had positive genetic testing, six families agreed to participate in this study. The participants were evaluated for ABCC8, KCNJ11, or HNF4 gene mutations by polymerase chain reaction (PCR) sequencing. The participants who were unresponsive to diazoxide and octreotide therapy received 0.5 mg/m/d of sirolimus, and the dose was gradually increased until a serum concentration of 5-15 ng/ml was achieved. Then, the participants were followed up for any possible complications.
RESULTS
Among the study participants, only one neonate was completely free of hypoglycemia after one year of follow-up, whereas three others experienced a partial reduction in hypoglycemic episodes over six months. One neonate underwent pancreatectomy despite receiving sirolimus. The oldest participant with a mutation in the ABCC8 gene responded well to sirolimus therapy after surgery and remained asymptomatic for 18 months.
CONCLUSION
This study suggested that sirolimus therapy needs further evaluation to determine which patients will benefit the most. The genetic basis of CHI may have possible implications for determining the patient's response.
PubMed: 32774365
DOI: 10.1155/2020/7250406 -
The Journal of Thoracic and... Jun 2022Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine...
OBJECTIVE
Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model.
METHODS
Twelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 μmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared.
RESULTS
Four pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P < .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P < .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL O/min, P = .12).
CONCLUSIONS
Diazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.
Topics: Animals; Adenosine Triphosphate; Cardioplegic Solutions; Diazoxide; Heart Arrest, Induced; Ischemia; Myocardial Ischemia; Myoglobin; Potassium; Potassium Channels; Stroke Volume; Swine; Troponin; Ventricular Function, Left
PubMed: 32977969
DOI: 10.1016/j.jtcvs.2020.08.069 -
PloS One 2019Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS.
METHOD
This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period.
RESULTS
Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide.
CONCLUSION
DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.
Topics: Adolescent; Basal Metabolism; Body Composition; Child; Delayed-Action Preparations; Diazoxide; Double-Blind Method; Female; Humans; Hyperinsulinism; Hyperphagia; Male; Obesity; Pilot Projects; Prader-Willi Syndrome; Safety; Waist Circumference; Young Adult
PubMed: 31545799
DOI: 10.1371/journal.pone.0221615 -
Journal of Cardiovascular Pharmacology Nov 2018The effects of diazoxide on cardiac hypertrophy and miR-132 expression were characterized in adult rats and in cardiomyocytes. Diazoxide effects on reactive oxygen...
INTRODUCTION AND METHODS
The effects of diazoxide on cardiac hypertrophy and miR-132 expression were characterized in adult rats and in cardiomyocytes. Diazoxide effects on reactive oxygen species (ROS) production and on the cAMP-response element binding (CREB) transcription factor's abundance in cardiomyocytes were also analyzed. ROS measurements used a fluorescent dye. Western blot analysis and quantitative Reverse Transcription Polymerase Chain Reaction were used to measure phosphorylated form of CREB (pCREB) abundance and miR-132 expression, respectively.
RESULTS
Isoproterenol (ISO) induced cardiac hypertrophy, an effect that was mitigated by diazoxide. The rate of ROS production, CREB phosphorylation, and miR-132 expression increased after the addition of ISO. H2O2 increased pCREB abundance and miR-132 expression; upregulation of miR-132 was blocked by the specific inhibitor of CREB transcription, 666-15. Consistent with a role of ROS on miR-132 expression, diazoxide prevented the increase in ROS production, miR-132 expression, and pCREB abundance produced by ISO. Phosphorylation of CREB by ISO was prevented by U0126, an inhibitor of mitogen-activated protein kinase.
CONCLUSIONS
Our data first demonstrate that diazoxide mitigates hypertrophy by preventing an increase in miR-132 expression. The mechanism likely involves less ROS production leading to less phosphorylation of CREB. Our data further show that ROS enhance miR-132 transcription, and that ISO effects are probably mediated by the mitogen-activated protein kinase pathway.
Topics: Animals; Animals, Newborn; Cardiomegaly; Cardiovascular Agents; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Diazoxide; Disease Models, Animal; Isoproterenol; Male; MicroRNAs; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Oxidative Stress; Phosphorylation; Rats, Wistar; Reactive Oxygen Species; Signal Transduction
PubMed: 30403388
DOI: 10.1097/FJC.0000000000000619 -
Acta Endocrinologica (Bucharest,... 2021Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic...
Hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by activating mutations in GLUD1 gene, and causes fasting as well as protein sensitive symptomatic hypoglycemia, in addition to persistently elevated plasma ammonia levels. First-line treatment is diazoxide, and most patients respond well to this agent, however side effects may be observed. The most frequent side effect of diazoxide is fluid retention and hypertrichosis, while hyperuricemia and hematologic side effects are observed less often. Herein, we report a case who had a heterozygous mutation of GLUD1 gene and who developed diazoxide related neutropenia 8 years after the start of treatment. On follow-up, leucopenia and mild neutropenia persisted and the treatment was changed to somatostatin analogues. However, she developed persistent severe symptomatic hypoglycemia and required diazoxide retreatment. A lower dose of diazoxide (6 mg/kg/day) successfully controlled hypoglycemia and cell counts increased even though they were not normalized. Neutropenia in current case presented after a long period of time of diazoxide use and this period is the longest defined in the literature. Long-term endocrine and hematologic follow-up of this patient up to 18 years old will also be presented.
PubMed: 35342475
DOI: 10.4183/aeb.2021.383 -
Clinical Pediatric Endocrinology : Case... 2021Hyperglycemia and hyperosmolar hyperglycemic syndrome (HHS) are the rare adverse effects of diazoxide. Furosemide has been reported to worsen glucose tolerance and cause...
Hyperglycemia and hyperosmolar hyperglycemic syndrome (HHS) are the rare adverse effects of diazoxide. Furosemide has been reported to worsen glucose tolerance and cause HHS. A 5-yr-old girl presented to the emergency department with complaints of tachycardia, polyuria, and lethargy for 1 wk prior to hospitalization. She was treated with two diuretics for aortic valve reflux disease and diazoxide for congenital hyperinsulinemia. She was diagnosed with HHS based on her serum glucose level of 529 mg/dL and serum osmotic pressure of 357 mOsm/kg. There were no findings suggestive of new-onset diabetes mellitus. She had fever on admission and, was diagnosed with a urinary tract infection. The blood diazoxide level at the time of hospitalization was 25 µg/dL. Diazoxide use, even in patients with low diazoxide levels, may cause hyperglycemia. Patients on diuretics and diazoxide must be carefully monitored, considering the risk of developing HHS.
PubMed: 34285456
DOI: 10.1297/cpe.30.139 -
International Journal of Molecular... Aug 2018Over the last decade it has become evident that under normal conditions connexin hemichannels are either not expressed (e.g., skeletal muscle) or are expressed in very...
Over the last decade it has become evident that under normal conditions connexin hemichannels are either not expressed (e.g., skeletal muscle) or are expressed in very low numbers with low open probability in various mammalian tissues (e.g., liver and central nervous system (CNS)).[...].
Topics: Adenosine Triphosphate; Animals; Anti-Inflammatory Agents; Biological Transport; Calcium; Cations, Divalent; Cell Communication; Connexin 43; Connexins; Diazoxide; Gap Junctions; Gene Expression Regulation; Humans; Inflammation; KATP Channels; Machine Learning; Peptide Fragments; Signal Transduction
PubMed: 30134552
DOI: 10.3390/ijms19092469 -
Clinical Endocrinology Dec 2019Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the...
OBJECTIVE
Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH.
DESIGN AND PATIENTS
Retrospective cohort study involving four UK regional HH centres; review of case notes of HH patients on diazoxide.
MEASUREMENTS
The diagnosis of PH was based on clinical and echocardiography evidence. Patient and treatment-related risk factors were analysed for association.
RESULTS
Thirteen (6 men) of 177 HH diazoxide-treated patients developed PH, an incidence of 7%. In the PH group, HH was diagnosed at median (range) of 9 (1,180) days, with diazoxide commenced 4 (0,76) days from diagnosis and reaching a maximum dose of 7 (2.5,20) mg/kg/d. The majority (8 of 13 patients) developed PH within 2 weeks of diazoxide. Complete diazoxide withdrawal, but not dose reduction, led to PH resolution at 41 (3,959) days. In three patients, PH continued beyond 12 months. Risk factors for the development of PH included the presence of congenital heart disease (CHD) (P = .008), and total fluid volume exceeding 130 mL/kg/d in the immediate 24 hours preceding diazoxide (P = .019).
CONCLUSION
Pulmonary hypertension can occur in 7% of diazoxide-treated HH patients. Risk factors include the presence of congenital heart disease and fluid overload. Recommendations include echocardiography and fluid restriction to 130 mL/kg/d prior to diazoxide treatment and immediate discontinuation of diazoxide if PH develops.
Topics: Congenital Hyperinsulinism; Diazoxide; Echocardiography; Female; Gestational Age; Humans; Hypertension, Pulmonary; Hypoglycemia; Male; Potassium Channels, Inwardly Rectifying; Retrospective Studies; Risk Factors; Sulfonylurea Receptors; United Kingdom
PubMed: 31520536
DOI: 10.1111/cen.14096 -
Clinics (Sao Paulo, Brazil) Feb 2017We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis.
OBJECTIVE:
We aimed to assess the effects of diazoxide on the mortality, pancreatic injury, and inflammatory response in an experimental model of acute pancreatitis.
METHODS:
Male Wistar rats (200-400 g) were divided randomly into two groups. Fifteen minutes before surgery, animals received physiological (0.9%) saline (3 mL/kg) (control group) or 45 mg/kg diazoxide (treatment group) via the intravenous route. Acute pancreatitis was induced by injection of 2.5% sodium taurocholate via the biliopancreatic duct. Mortality (n=38) was observed for 72 h and analyzed by the Mantel-Cox Log-rank test. To study pancreatic lesions and systemic inflammation, rats (10 from each group) were killed 3 h after acute pancreatitis induction; ascites volume was measured and blood as well as pancreases were collected. Pancreatic injury was assessed according to Schmidt's scale. Cytokine expression in plasma was evaluated by the multiplex method.
RESULTS:
Mortality at 72 h was 33% in the control group and 60% in the treatment group (p=0.07). Ascites volumes and plasma levels of cytokines between groups were similar. No difference was observed in edema or infiltration of inflammatory cells in pancreatic tissues from either group. However, necrosis of acinar cells was lower in the treatment group compared to the control group (3.5 vs. 3.75, p=0.015).
CONCLUSIONS:
Treatment with diazoxide can reduce necrosis of acinar cells in an experimental model of acute pancreatitis, but does not affect the inflammatory response or mortality after 72 h.
Topics: Animals; Cholagogues and Choleretics; Diazoxide; Disease Models, Animal; Male; Pancreatitis, Acute Necrotizing; Random Allocation; Rats; Rats, Wistar; Taurocholic Acid; Vasodilator Agents
PubMed: 28273237
DOI: 10.6061/clinics/2017(02)10 -
The Journal of Clinical Endocrinology... Dec 2018Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has... (Observational Study)
Observational Study
CONTEXT
Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety of this drug. Existing reports are limited to small studies and case reports.
OBJECTIVE
To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide.
DESIGN
Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014.
SETTING
The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia.
PATIENTS
Children and infants with laboratory-confirmed diagnosis of HI.
MAIN OUTCOME MEASURES
Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors.
RESULTS
A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P < 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%).
CONCLUSION
In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide.
Topics: Congenital Hyperinsulinism; Diazoxide; Dose-Response Relationship, Drug; Drug Administration Schedule; Edema; Female; Gestational Age; Humans; Hypertension, Pulmonary; Hyperuricemia; Infant; Infant, Newborn; Infant, Premature; Insulin; Insulin Secretion; KATP Channels; Male; Neutropenia; Prevalence; Retrospective Studies; Risk Factors; Thrombocytopenia
PubMed: 30247666
DOI: 10.1210/jc.2018-01613