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The Journal of Thoracic and... Jun 2018
Topics: Diazoxide; Erythropoietin; Humans; Paraplegia; Spinal Cord
PubMed: 29409604
DOI: 10.1016/j.jtcvs.2017.12.115 -
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 -
British Medical Journal Oct 1975
Topics: Adolescent; Clonidine; Diazoxide; Diuresis; Female; Furosemide; Heart Rate; Humans; Hypertension
PubMed: 1174908
DOI: 10.1136/bmj.4.5987.23 -
Pediatric Diabetes Aug 2018Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the...
BACKGROUND
Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited.
OBJECTIVE
To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes.
DESIGN
Retrospective descriptive study.
METHODS
Medical records were reviewed to extract clinical information. Mutation analysis was carried out for 8 genes associated with HI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF4A, HNF1A, and UCP2).
RESULTS
HNF1A and HNF4A mutations were identified in 5.9% (12 out of 204; HNF1A = 7, HNF4A = 5) of diazoxide-responsive HI probands. The clinical phenotypes were extremely variable. Two children showed evidence of ketone production during hypoglycemia, a biochemical profile atypical for hyperinsulinism. At the time of analysis, diazoxide was discontinued in 5 children at a median age of 6.8 years. None had developed diabetes mellitus at a median age of 7.0 years.
CONCLUSIONS
Given the heterogeneous clinical phenotypes of HNF1A- and HNF4A-HI, all children with transient, diazoxide-responsive HI without clear history of perinatal stress, should be screened for HNF1A and HNF4A mutations as it predicts the clinical course and affects the subsequent management plan.
Topics: Child; Diazoxide; Female; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 4; Humans; Hyperinsulinism; Male; Mutation; Retrospective Studies
PubMed: 29493090
DOI: 10.1111/pedi.12655 -
Pediatric Annals Mar 2014A male patient was born small for gestational age (SGA) at 33 weeks with a birth weight of 1,663 grams (< 10th percentile) and length 43 cm (10th percentile) to a...
A male patient was born small for gestational age (SGA) at 33 weeks with a birth weight of 1,663 grams (< 10th percentile) and length 43 cm (10th percentile) to a 38-year-old G5P4 mother by cesarean section due to non-reassuring fetal heart tones. Prior to delivery, his mother experienced decreased fetal movement and decelerations. At birth, he was initially well-appearing and vigorous, with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively. The physical examination was unremarkable--no skin findings, no facial anomalies, good tone, and the anterior fontanelle was soft and flat. The placenta, although noted to be healthy in appearance on prenatal ultrasounds, was atrophic and calcified by gross examination. The patient developed respiratory distress 1 hour after birth and was found to have a blood glucose level of 24 mg/dL. Following an intravenous (IV) bolus of 10% dextrose in water (D10W) of 2 mL/kg, his glucose was 20 mg/dL. He was started on IV fluids with a glucose infusion rate (GIR) of 7.3 mg/kg/minute, with a subsequent rise in blood glucose to 46 mg/dL. Due to prematurity, respiratory distress, and persistent hypoglycemia, a diagnostic evaluation was initiated for possible sepsis, including a complete blood count with differential and platelet count and blood cultures. The patient was started empirically on IV ampicillin and gentamicin. The patient was subsequently found to have thrombocytopenia, hypomagnesemia, and hyponatremia on laboratory evaluation and was transferred to our neonatal intensive care unit (NICU) for further care.
Topics: Blood Glucose; Diagnosis, Differential; Diazoxide; Humans; Hyperinsulinism; Infant, Newborn; Infant, Premature, Diseases; Infant, Small for Gestational Age; Intensive Care, Neonatal; Male; Premature Birth
PubMed: 24605860
DOI: 10.3928/00904481-20140221-08 -
Endocrine Journal 2016Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension....
Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia.
Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Diazoxide; Drug Monitoring; Drug Resistance; Edema; Female; Heart Failure; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Japan; Male; Middle Aged; Water-Electrolyte Imbalance
PubMed: 26598136
DOI: 10.1507/endocrj.EJ15-0428 -
British Journal of Pharmacology Sep 19881. The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch-clamp...
1. The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch-clamp methods in an insulin-secreting cell line derived from a rat islet cell tumour. 2. Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2-5 fold. The concentrations of tolbutamide and glibenclamide giving half-maximum effects on insulin secretion were approximately 40 microM and 0.2 microM, respectively. 3. Diazoxide (0.6-1.0 mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20 mM), it produced inhibition. Tolbutamide-induced release was also inhibited by diazoxide. 4. Tolbutamide, glibenclamide, HB699 and HB985 reduced the open-state probability of the ATP-K+ channel in a dose-dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied. 5. In whole cell recording, in which the total ATP-sensitive K+ conductance of the cell could be measured, dose-inhibition curves for tolbutamide and glibenclamide were constructed, resulting in Ki values of 17 microM and 27 nM, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6. Diazoxide (0.6 mM) activated the ATP-K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3-30 microM). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7. Neither tolbutamide (1.0 mM) nor glibenclamide (10 microM) altered the open-state probability of the Ca2+-activated K+ channel or the Ca2+-activated non-selective cation channel which are present in this cell line. 8. It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP-K+ channel or a protein closely associated with this channel.
Topics: Adenosine Triphosphate; Animals; Cell Line; Diazoxide; Electrophysiology; Glucose; Glyburide; Insulin; Insulin Secretion; Islets of Langerhans; Leucine; Nucleotides; Potassium Channels; Rats; Sulfonylurea Compounds; Tolbutamide
PubMed: 3146398
DOI: 10.1111/j.1476-5381.1988.tb16551.x -
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 -
European Journal of Pharmacology Oct 2021Mitochondrial ATP-sensitive potassium channels (mitoKATP) locate in the inner mitochondrial membrane and possess protective cellular properties. mitoKATP opening-induced...
Pharmacological and molecular docking studies reveal that glibenclamide competitively inhibits diazoxide-induced mitochondrial ATP-sensitive potassium channel activation and pharmacological preconditioning.
Mitochondrial ATP-sensitive potassium channels (mitoKATP) locate in the inner mitochondrial membrane and possess protective cellular properties. mitoKATP opening-induced cardioprotection (using the pharmacological agent diazoxide) is preventable by antagonists, such as glibenclamide. However, the mechanisms of action of these drugs and how mitoKATP respond to them are poorly understood. Here, we show data that reinforce the existence of a mitochondrial sulfonylurea receptor (mitoSUR) as part of the mitoKATP. We also show how diazoxide and glibenclamide compete for the same binding site in mitoSUR. A glibenclamide analog that lacks its cyclohexylurea portion (IMP-A) loses its ability to inhibit diazoxide-induced swelling. These results suggest that the cyclohexylureia portion of glibenclamide is indispensable for mitoKATP inhibition. Moreover, IMP-A did not suppress diazoxide-induced preconditioning (EC50 10.66 μM) in a rat model of a cardiac ischemia/reperfusion. Importantly, glibenclamide inhibited both diazoxide-induced cardioprotection (IC50 86 nM). We suggest that IMP-A must be used with caution since we found this drug possesses significant inhibitory effects on mitochondrial respiration. We characterized the binding of glibenclamide and diazoxide using a molecular simulation (docking) approach. Using the molecular structure of the ATP binding protein ABCB8 (pointed by others as the mitoSUR) we demonstrate that glibenclamide competitively inhibits diazoxide actions. This was reinforced (pharmacologically) in a competitive antagonism test. Taken together, these results bring valuable and novel insights into the pharmacological/biochemical aspects of mitokATP activation and cardioprotection. This study may lead to the discovery of novel therapeutic strategies that may impact ischemia-reperfusion injury.
Topics: Animals; Diazoxide; Glyburide; KATP Channels; Molecular Docking Simulation; Rats
PubMed: 34324857
DOI: 10.1016/j.ejphar.2021.174379 -
Hormone Research in Paediatrics 2017Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with...
BACKGROUND
Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI.
METHODS
We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated.
RESULTS
Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration.
CONCLUSION
We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.
Topics: Adolescent; Child; Child, Preschool; Congenital Hyperinsulinism; Diazoxide; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Male; Models, Biological
PubMed: 28715810
DOI: 10.1159/000478696