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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 -
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 -
Paediatric Drugs Jun 2019Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycmia in neonatles and children. The inappropriate secretion of insulin by the pancreatic... (Review)
Review
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycmia in neonatles and children. The inappropriate secretion of insulin by the pancreatic β-cells produces recurrent hypoglycemia, which can lead to severe and permanent brain damage. CHI results from mutations in different genes that play a role in the insulin secretion pathway, and each differs in their responsiveness to medical treatment. Currently, the only available approved treatment for hyperinsulinism is diazoxide. Patients unresponsive to diazoxide may benefit from specialized evaluation including genetic testing and 18F-DOPA PET to identify those with focal forms of CHI. The focal forms can be cured by selective pancreatectomy, but the management of diazoxide-unresponsive diffuse CHI is a real therapeutic challenge. Current off-label therapies include intravenous glucagon, octreotide and long-acting somatostatin analogs; however, they are often insufficient, and a 98% pancreatectomy or continuous feeds may be required. For the first time in over 40 years, new drugs are being developed, but none have made it to market yet. In this review, we will discuss current on-label and off-label drugs and review the currently available data on the novel drugs under development.
Topics: Child; Congenital Hyperinsulinism; Humans; Hypoglycemia
PubMed: 31218604
DOI: 10.1007/s40272-019-00334-w -
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 -
American Journal of Respiratory Cell... May 2022Mutations in have been identified in pulmonary arterial hypertension (PAH). encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However,...
Mutations in have been identified in pulmonary arterial hypertension (PAH). encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analyzed the expression of SUR1/Kir6.2 in the lungs and pulmonary artery (PA) in human PAH or experimental pulmonary hypertension (PH). The contribution of SUR1 in human or rat PA tone was evaluated, and we measured the consequences of activation of SUR1 in control and PH rats. SUR1 and Kir6.2 protein expression was not reduced in the lungs or human pulmonary arterial endothelial cells and smooth muscle cells from PAH or experimentally induced PH. We showed that pharmacological activation of SUR1 by three different SUR1 activators (diazoxide, VU0071063, and NN414) leads to PA relaxation. Conversely, the inhibition of SUR1/Kir6.2 channels causes PA constriction. long- and short-term activation of SUR1 with diazoxide reversed monocrotaline-induced PH in rats. In addition, diazoxide application (short protocol) reduced the severity of PH in chronic-hypoxia rats. Moreover, 3 weeks of diazoxide exposure in control rats had no cardiovascular effects. Finally, , activation of SUR1 with NN414 reduced monocrotaline-induced PH in rats. In PAH and experimental PH, the expression of SUR1/Kir6.2 was still present. pharmacological SUR1 activation by two different molecules alleviated experimental PH, providing proof of concept that SUR1 activation should be considered for PAH and evaluated more thoroughly.
Topics: Animals; Diazoxide; Endothelial Cells; Familial Primary Pulmonary Hypertension; Monocrotaline; Pulmonary Arterial Hypertension; Rats
PubMed: 35175177
DOI: 10.1165/rcmb.2021-0180OC -
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 -
Acta Chirurgica Belgica Apr 2022Surgery is the ideal treatment of insulinoma. However, systemic therapy may be required to prevent severe preoperative hypoglycaemia, when surgery is contraindicated,...
Surgery is the ideal treatment of insulinoma. However, systemic therapy may be required to prevent severe preoperative hypoglycaemia, when surgery is contraindicated, delayed or refused and in case of unresectable metastatic disease. Diazoxide is commonly used but is not always effective and can cause serious side effects. Somatostatin analogues (octreotide and lanreotide) may be an alternative option. We report the case of a 27-year-old patient with insulinoma in whom diazoxide was compared with lanreotide before operation. A diagnosis of insulinoma was made on the basis of a fasting test and a 2 cm tumour confirmed in the body of the pancreas, with a high uptake of 111-In-pentreotide. Diazoxide was initiated and increased to a maximal tolerated dose of 450 mg/day. Because of dyspnoea and persisting hypoglycaemia, diazoxide was shifted to lanreotide 120 mg. All symptoms resolved without hypoglycaemia. According to the EORTC quality score of life, the score without treatment, under diazoxide, under lanreotide and after surgery were respectively 84.7, 73.3, 90.9 and 99.1. Thus, providing a positive Octreoscan, somatostatin analogues may be a safe, effective and well-tolerated option in patients with insulinoma refractory and/or intolerant to diazoxide or with a high risk of fluid retention.
Topics: Adult; Diazoxide; Humans; Insulinoma; Octreotide; Pancreatic Neoplasms; Somatostatin
PubMed: 32375590
DOI: 10.1080/00015458.2020.1765676 -
European Review For Medical and... Sep 2018The endoplasmic reticulum (ER) -resident caspase-12 was identified as a mediator of Aβ neurotoxicity. Recent evidence indicates that mitochondrial ATP-sensitive...
OBJECTIVE
The endoplasmic reticulum (ER) -resident caspase-12 was identified as a mediator of Aβ neurotoxicity. Recent evidence indicates that mitochondrial ATP-sensitive potassium (KATP) channel openers mediate their neuroprotective role by adjusting ER stress pathways, but the molecular details remain largely unknown and have been investigated.
MATERIALS AND METHODS
In this study, the protein expression levels of calreticulin (CRT) and caspase-12 activation and phosphorylated p38 MAPK were observed by immunoblotting in cultured PC12 cells from different groups: treatment with Aβ25-35 (group Aβ25-35), treatment with diazoxide (group diazoxide), pretreatment with diazoxide and then exposure to Aβ25-35 (group diazoxide + Aβ25-35), pretreatment with p38 MAPK inhibitor SB 203580 and then exposure to diazoxide and Aβ25-35 (group SB 203580 + diazoxide + Aβ25-35), and the control (group control).
RESULTS
In response to the treatment with Aβ25-35 (10 µM) for 24 h, the protein expression levels of CRT and caspase-12 activation were increased and phosphorylated p38 MAPK was decreased significantly. Diazoxide reduced CRT overexpression and caspase-12 activation and increased the up-regulation of phosphorylated p38 MAPK. When SB 203580 was presented before exposure to diazoxide and Aβ25-35, CRT expression was markedly suppressed, and the inhibition effect of diazoxide on caspase-12 activation was almost eliminated.
CONCLUSIONS
We showed that diazoxide induced ERS-related neuroprotection mediated by p38 MAPK against Aβ25-35 insults. From the clinical point of view, these results are of considerable importance for the understanding of AD pathogenesis. However, further studies are required to explore more detailed mechanisms of the observed effects.
Topics: Amyloid beta-Peptides; Animals; Apoptosis; Caspase 12; Diazoxide; Endoplasmic Reticulum Stress; Neuroprotection; PC12 Cells; Peptide Fragments; Rats; p38 Mitogen-Activated Protein Kinases
PubMed: 30280801
DOI: 10.26355/eurrev_201809_15953 -
Clinical Medicine Insights. Case Reports 2023Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We...
Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We reported a 37-week-old boy with the diagnosis of hypoglycemia. We started a dextrose infusion, but we used oral diazoxide, due to hypoglycemia episodes despite the increase in dextrose intake. The newborn had a normoglycemic condition after gradually increasing the diazoxide dose to 15 mg/kg/day. He was fully breastfed and discharged at 14 days of age with ongoing diazoxide. In weekly serial clinical follow-ups, the parents noticed an increase in the growth of forehead and facial hair that was diagnosed as diazoxide-induced hypertrichosis. Diazoxide was gradually tapered, and hypertrichosis continued until 1 month after dioxide discontinuation. Diazoxide use in NICU settings has increased over time. Diazoxide has many side effects, one of which is hypertrichosis. Many diazoxide side effects have been reported in adults or children and few studies have reported the prevalence of these adverse effects of diazoxide in neonates and infants.
PubMed: 36726424
DOI: 10.1177/11795476231151330 -
Archives of Disease in Childhood. Fetal... Jul 2022Diazoxide (DZX) is the drug of choice for treating hyperinsulinaemic hypoglycaemia (HH), and it has potentially serious adverse effects. We studied the safety and... (Observational Study)
Observational Study
OBJECTIVES
Diazoxide (DZX) is the drug of choice for treating hyperinsulinaemic hypoglycaemia (HH), and it has potentially serious adverse effects. We studied the safety and efficacy of low-dose DZX in small-for-gestational-age (SGA) infants with HH.
DESIGN
An observational cohort study from 1 September 2014 to 31 September 2020.
SETTING
A tertiary Women's and Children's Hospital in Singapore.
PATIENTS
All SGA infants with HH.
INTERVENTION
Diazoxide, at 3-5 mg/kg/day.
MAIN OUTCOME MEASURES
Short-term outcomes; adverse drug events and fasting studies to determine 'safe to go home' and 'resolution' of HH.
RESULTS
Among 71 836 live births, 11 493 (16%) were SGA. Fifty-six (0.5%) SGA infants with HH were identified, of which 27 (47%) with a mean gestational age of 36.4±2 weeks and birth weight of 1942±356 g required DZX treatment. Diazoxide was initiated at 3 mg/kg/day at a median age of 10 days. The mean effective dose was 4.6±2.2 mg/kg/day, with 24/27 (89%) receiving 3-5 mg/kg/day. Generalised hypertrichosis occurred in 2 (7.4%) and fluid retention in 1 (3.7%) infant. A fasting study was performed before home while on DZX in 26/27 (96%) cases. Diazoxide was discontinued at a median age of 63 days (9-198 days), and resolution of HH was confirmed in 26/27 (96%) infants on passing a fasting study.
CONCLUSION
Our study demonstrates that low-dose DZX effectively treats SGA infants with HH as measured by fasting studies. Although the safety profile was excellent, minimal adverse events were still observed with DZX, even at low doses.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age
PubMed: 34544689
DOI: 10.1136/archdischild-2021-322845