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Therapeutic Advances in Drug Safety 2021The most common cause of persistent hypoglycemia in infancy is hyperinsulinemic hypoglycemia. When conservative measures fail, providers often use medications to treat...
BACKGROUND
The most common cause of persistent hypoglycemia in infancy is hyperinsulinemic hypoglycemia. When conservative measures fail, providers often use medications to treat persistent hypoglycemia. Diazoxide is first-line therapy for neonatal hypoglycemia and works by inhibiting insulin secretion. Diazoxide is associated with fluid retention, and less commonly with respiratory decompensation and pulmonary hypertension. Case reports documenting these severe adverse events exist in the literature, although the overall incidence, risk factors, and timing for these effects in a newborn are not clearly defined.
METHODS
We performed a retrospective chart review of all infants admitted to the neonatal intensive care unit (NICU) at Regional One Health from 1 January 2013 until 15 August 2019, who received diazoxide as a treatment for persistent hypoglycemia secondary to hyperinsulinism. Patients were stratified as either having no adverse event or having an adverse outcome to the medication. A severe adverse outcome was defined as any known major side effect of the medication, which a patient developed within 2 weeks of medication initiation that led to medication discontinuation.
RESULTS
From our pharmacy database, we identified a total of 15 babies who received diazoxide for persistent hypoglycemia. Of these patients, eight (53%) were classified as having a complication requiring discontinuation of the medication. Six out of eight patients required intubation with mechanical ventilation and five out of eight patients developed pulmonary hypertension. All patients returned to their baseline respiratory support after drug discontinuation.
CONCLUSIONS
A total of 53% of our study population had an adverse outcome to diazoxide. Previous studies suggest 5% of patients may have respiratory decompensation and require ventilatory support while on diazoxide; however, 40% of our patients deteriorated and then required mechanical ventilation. Based on our data, respiratory deterioration may be more likely to occur when diazoxide is used in preterm infants, those with lower birth weight and intrauterine growth restriction.
PLAIN LANGUAGE SUMMARY
Newborns could experience a transient period of low blood glucose levels soon after birth. However, some may progress to persistent low blood glucose levels that cannot be controlled with adequate glucose infusion and may require other ways of treatment. Diazoxide is the first-line drug approved by the US Food and Drug Administration (FDA) for this condition. However, certain cases have reported the development of respiratory deterioration, including increased blood pressure in lung circulation after its use. This prompted a black box warning in 2015 by the FDA. The incidence of neonatal low blood glucose levels seems to have increased and so has the use of this drug. Our study identifies 15 newborns who received diazoxide at Regional One Health neonatal intensive care unit in the past 6 years and reports a significantly higher rate of adverse events in our population leading to drug discontinuation in almost 53% of our cases.
PubMed: 34046157
DOI: 10.1177/20420986211011338 -
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 -
The Journal of Clinical Endocrinology... Mar 2016Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as... (Review)
Review
CONTEXT
Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as 25-50% due to delays in diagnosis and inadequate treatment. Congenital HI has been described since the birth of the JCEM under various terms, including "idiopathic hypoglycemia of infancy," "leucine-sensitive hypoglycemia," or "nesidioblastosis."
EVIDENCE ACQUISITION
In the past 20 years, it has become apparent that HI is caused by genetic defects in the pathways that regulate pancreatic β-cell insulin secretion.
EVIDENCE SYNTHESIS
There are now 11 genes associated with monogenic forms of HI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1), as well as several syndromic genetic forms of HI (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). HI is also the cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as birth asphyxia, small for gestational age birthweight, infant of diabetic mother). Management of HI is one of the most difficult problems faced by pediatric endocrinologists and frequently requires difficult choices, such as near-total pancreatectomy and/or highly intensive care with continuous tube feedings. For 50 years, diazoxide, a KATP channel agonist, has been the primary drug for infants with HI; however, it is ineffective in most cases with mutations of ABCC8 or KCNJ11, which constitute the majority of infants with monogenic HI.
CONCLUSIONS
Genetic mutation testing has become standard of care for infants with HI and has proven to be useful not only in projecting prognosis and family counseling, but also in diagnosing infants with surgically curable focal HI lesions. (18)F-fluoro-L-dihydroxyphenylalanine ((18)F-DOPA) PET scans have been found to be highly accurate for localizing such focal lesions preoperatively. New drugs under investigation provide hope for improving the outcomes of children with HI.
Topics: Congenital Hyperinsulinism; Humans; Infant, Newborn; Insulin; Insulin Secretion; KATP Channels
PubMed: 26908106
DOI: 10.1210/jc.2015-3651 -
JAMA Network Open Jun 2024Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment.
OBJECTIVE
To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia.
DESIGN, SETTING, AND PARTICIPANTS
This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours).
INTERVENTIONS
Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol.
MAIN OUTCOME AND MEASURES
The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks.
RESULTS
Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo.
TRIAL REGISTRATION
ANZCTR.org.au Identifier: ACTRN12620000129987.
Topics: Humans; Diazoxide; Hypoglycemia; Infant, Newborn; Female; Male; New Zealand; Recurrence; Blood Glucose; Treatment Outcome
PubMed: 38869900
DOI: 10.1001/jamanetworkopen.2024.15764 -
Frontiers in Cardiovascular Medicine 2021Previous studies have shown that diazoxide can protect against myocardial ischemia-reperfusion injury (MIRI). The intranuclear hypoxia-inducible factor-1...
Previous studies have shown that diazoxide can protect against myocardial ischemia-reperfusion injury (MIRI). The intranuclear hypoxia-inducible factor-1 (HIF-1)/hypoxia-response element (HRE) pathway has been shown to withstand cellular damage caused by MIRI. It remains unclear whether diazoxide post-conditioning is correlated with the HIF-1/HRE pathway in protective effect on cardiomyocytes. An isolated cardiomyocyte model of hypoxia-reoxygenation injury was established. Prior to reoxygenation, cardiomyocytes underwent post-conditioning treatment by diazoxide, and 5-hydroxydecanoate (5-HD), N-(2-mercaptopropionyl)-glycine (MPG), or dimethyloxallyl glycine (DMOG) followed by diazoxide. At the end of reoxygenation, ultrastructural morphology; mitochondrial membrane potential; interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), reactive oxygen species (ROS), and HIF-1α levels; and downstream gene mRNA and protein levels were analyzed to elucidate the protective mechanism of diazoxide post-conditioning. Diazoxide post-conditioning enabled activation of the HIF-1/HRE pathway to induce myocardial protection. When the mitoK channel was inhibited and ROS cleared, the diazoxide effect was eliminated. DMOG was able to reverse the effect of ROS absence to restore the diazoxide effect. MitoK and ROS in the early reoxygenation phase were key to activation of the HIF-1/HRE pathway. Diazoxide post-conditioning promotes opening of the mitoK channel to generate a moderate ROS level that activates the HIF-1/HRE pathway and subsequently induces myocardial protection.
PubMed: 34938777
DOI: 10.3389/fcvm.2021.711465 -
Evidence-based Complementary and... 2019This study was aimed to investigate whether ginsenoside Rb1 (GS-Rb1) from the cardioprotective Chinese medicine ginseng can reduce hypoxia-reoxygenation (HR)-induced...
This study was aimed to investigate whether ginsenoside Rb1 (GS-Rb1) from the cardioprotective Chinese medicine ginseng can reduce hypoxia-reoxygenation (HR)-induced damage to cardiomyocytes by protecting the mitochondria. Mitochondria-mediated apoptosis plays a key role during myocardial ischemia-reperfusion injury (MIRI). When MIRI occurs, the continuous opening of the mitochondrial permeability transition pore (mPTP) causes mitochondrial damage and ultimately leads to apoptosis. We treated H9c2 cells, derived from rat embryonic cardiomyoblasts, with GS-Rb1, diazoxide, and 5-hydroxydecanoate (5-HD), using HR to simulate MIRI. We found that GS-Rb1 can reduce mPTP by stabilizing the mitochondrial membrane potential (MMP) and by reducing reactive oxygen species (ROS) during HR. This protects the mitochondria by reducing the release of cytochrome c and the expression of cleaved-caspase-3 in the cytoplasm, ultimately reducing apoptosis. During this process, GS-Rb1 and diazoxide showed similar effects. These findings provide some evidence for a protective effect of GS-Rb1 treatment on MIRI.
PubMed: 31915449
DOI: 10.1155/2019/6046405 -
Investigative Ophthalmology & Visual... Feb 2022To evaluate the effect of ATP-sensitive potassium channel openers cromakalim prodrug 1 (CKLP1) and diazoxide on IOP in three independent mouse models of ocular...
PURPOSE
To evaluate the effect of ATP-sensitive potassium channel openers cromakalim prodrug 1 (CKLP1) and diazoxide on IOP in three independent mouse models of ocular hypertension.
METHODS
Baseline IOP was measured in TGFβ2 overexpression, steroid-induced, and iris dispersion (DBA/2J) ocular hypertension mouse models, followed by once daily eyedrop administration with CKLP1 (5 mM) or diazoxide (5 mM). The IOP was measured in conscious animals with a handheld rebound tonometer. Aqueous humor dynamics were assessed by a constant perfusion method. Effect of treatment on ocular tissues was evaluated by transmission electron microscopy.
RESULTS
CKLP1 decreased the IOP by 20% in TGFβ2 overexpressing mice (n = 6; P < 0.0001), 24% in steroid-induced ocular hypertensive mice (n = 8; P < 0.0001), and 43% in DBA/2J mice (n = 15; P < 0.0001). Diazoxide decreased the IOP by 32% in mice with steroid-induced ocular hypertension (n = 13; P < 0.0001) and by 41% in DBA/2J mice (n = 4; P = 0.005). An analysis of the aqueous humor dynamics revealed that CKLP1 decreased the episcleral venous pressure by 29% in TGFβ2 overexpressing mice (n = 13; P < 0.0001) and by 72% in DBA/2J mice (n = 4 control, 3 treated; P = 0.0002). Diazoxide lowered episcleral venous pressure by 35% in steroid-induced ocular hypertensive mice (n = 3; P = 0.03). Tissue histology and cell morphology appeared normal when compared with controls. Accumulation of extracellular matrix was reduced in CKLP1- and diazoxide-treated eyes in the steroid-induced ocular hypertension model.
CONCLUSIONS
ATP-sensitive potassium channel openers CKLP1 and diazoxide effectively decreased the IOP in ocular hypertensive animal models by decreasing the episcleral venous pressure, supporting a potential therapeutic application of these agents in ocular hypertension and glaucoma.
Topics: Animals; Antihypertensive Agents; Cromakalim; Diazoxide; Disease Models, Animal; Eye; Intraocular Pressure; KATP Channels; Mice; Mice, Inbred DBA; Microscopy, Electron, Transmission; Ocular Hypertension; Ophthalmic Solutions
PubMed: 35129587
DOI: 10.1167/iovs.63.2.15 -
Physiological Reports Apr 2024High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an...
High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an antihypertensive agent that inhibits insulin secretion and is an opener of K channels (adosine triphosphate sensitive potasium channels). For this reason, it is hypothesized that moderate-intensity exercise and diazoxide improve skeletal muscle function by reducing the oxidants in hypertensive rats. Male Wistar rats were assigned into eight groups: control (CTRL), diazoxide (DZX), exercise (EX), exercise + diazoxide (EX + DZX), hypertension (HTN), hypertension + diazoxide (HTN + DZX), hypertension + exercise (HTN + EX), and hypertension + exercise + diazoxide (HTN + EX + DZX). To induce hypertension, the rats received 8% NaCl dissolved in water orally for 30 days; in the following 8 weeks, 4% NaCl was supplied to maintain the pathology. The treatment with physical exercise of moderate intensity lasted 8 weeks. The administration dose of diazoxide was 35 mg/kg intraperitoneally for 14 days. Tension recording was performed on the extensor digitorum longus and the soleus muscle. Muscle homogenates were used to measure oxidants using fluorescent probe and the activity of antioxidant systems. Diazoxide and moderate-intensity exercise reduced oxidants and increased antioxidant defenses.
Topics: Animals; Diazoxide; Male; Muscle, Skeletal; Rats, Wistar; Hypertension; Physical Conditioning, Animal; Rats; Antioxidants; Oxidative Stress; Oxidants
PubMed: 38653584
DOI: 10.14814/phy2.16026 -
Diabetes Mar 2022Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by... (Review)
Review
Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.
Topics: Animals; Blood Glucose; Calcium; Congenital Hyperinsulinism; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin Secretion; KATP Channels; Mice; Mice, Knockout; Mutation; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors
PubMed: 35196393
DOI: 10.2337/db21-0755 -
Future Medicinal Chemistry May 2016ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g.,... (Review)
Review
ATP-sensitive potassium (KATP) channels play fundamental roles in the regulation of endocrine, neural and cardiovascular function. Small-molecule inhibitors (e.g., sulfonylurea drugs) or activators (e.g., diazoxide) acting on SUR1 or SUR2 have been used clinically for decades to manage the inappropriate secretion of insulin in patients with Type 2 diabetes, hyperinsulinism and intractable hypertension. More recently, the discovery of rare disease-causing mutations in KATP channel-encoding genes has highlighted the need for new therapeutics for the treatment of certain forms of neonatal diabetes mellitus, congenital hyperinsulinism and Cantu syndrome. Here, we provide a high-level overview of the pathophysiology of these diseases and discuss the development of a flexible high-throughput screening platform to enable the development of new classes of KATP channel modulators.
Topics: Adenine Nucleotides; Animals; Cardiomegaly; Channelopathies; Diabetes Mellitus, Type 2; Humans; Hyperinsulinism; Hypertrichosis; Hypoglycemic Agents; Ion Channel Gating; KATP Channels; Osteochondrodysplasias; Protein Transport
PubMed: 27161588
DOI: 10.4155/fmc-2016-0005