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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 -
Cellular and Molecular Biology... Jul 2018Cardiac hypertrophy is associated with mitochondrial dysfunctions, which leads to heart failure if sustained. The aim of present study is to test hypothesis whether...
Cardiac hypertrophy is associated with mitochondrial dysfunctions, which leads to heart failure if sustained. The aim of present study is to test hypothesis whether activation of mitochondrial KATP channel (mitoKATP) by diazoxide improve mitochondrial membrane potential (MMP) and oxidative stress in an in vitro model of cardiac hypertrophy. Rat cardiomyocytes cell line (H9c2) was used to create four groups as control, diazoxide, hypertrophy, hypertrophy and diazoxide. Norepinephrine was used to induce hypertrophy. Diazoxide and norepinephrine were simultaneously administered. After 24 hours treatment, total oxidant status (TOS), total antioxidant status (TAS) and superoxide dismutase (SOD) activities were measured. MMP and F-actin distribution were analyzed. Hypertrophy significantly elevated TOS level. In addition, diazoxide administration significantly increased TOS level in the normal cell line. There were no significant differences in SOD activity, TAS and oxidative stress index (OSI) between groups. Hypertrophy caused a decrease in MMP and destrupted F-actin. Diazoxide improved MMP and F-actin in mitochondria. Hypertrophy impaired the function and structure of mitochondria. The opening of mitoKATP by diazoxide failed to improve oxidative stress; however, it is effective against mitochondrial damage caused by hypertrophy.
Topics: Animals; Cardiomegaly; Cell Line; Diazoxide; Membrane Potential, Mitochondrial; Mitochondria; Norepinephrine; Oxidative Stress; Potassium Channels; Rats
PubMed: 30084794
DOI: No ID Found -
Journal of Bioenergetics and... Feb 2023Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral...
AIM/INTRODUCTION
Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Hyperglycemia causes dyslipidemia and stimulates oxidative damage, leading to the main symptoms, such as fatigue and culminates in diabetic complications. Previous studies have shown that ATP-sensitive potassium channels counteract muscle fatigue and metabolic stress in healthy mouse models. To determine the effect of diazoxide on muscle strength development during diabetes, we tested the effect of diazoxide in streptozotocin-diabetic rats in muscle function, lipid profile and oxidative stress biomarkers.
MATERIALS AND METHODS
Wistar rats were divided into 4 groups of six animals each: (1) Control group, (2) diabetes group, (3) Control group + diazoxide, and (4) Diabetic + diazoxide (DB + DZX). 4 weeks after rats were sacrificed, soleus and extensor digitorum longus muscles (EDL) were extracted to prepare homogenates and serum was obtained for biochemical measurements. Oxidative damage was evaluated by the thiobarbituric acid method and the fluorescent for reactive oxygen species (ROS) probe 2,4-HDCFDA, respectively.
RESULTS
Diabetic rats with diazoxide administration showed an increase in the development of muscle strength in both muscles; in turn, the onset of fatigue was longer compared to the group of diabetic rats without treatment. Regarding the lipid profile, diazoxide decreased total cholesterol levels in the group of diabetic rats treated with diazoxide (x̅46.2 mg/dL) compared to the untreated diabetic group (x̅=104.4 mg/dL); secondly, diazoxide decreased triglyceride concentrations (x̅=105.3 mg/dL) compared to the untreated diabetic rats (x̅=412.2 mg/dL) as well as the levels of very low-density lipoproteins (x̅=20.4 mg/dL vs. x̅=82.44 mg/dL). Regarding the various markers of oxidative stress, the diabetic group treated with diazoxide was able to reduce the concentrations of TBARS and total reactive oxygen species as well as preserve the concentrations of reduced glutathione.
CONCLUSION
Diazoxide administration in diabetic rats increases muscle strength development in EDL and soleus muscle, decreases fatigue, reduces cholesterol and triglyceride concentrations and improves oxidative stress parameters such as TBARS, ROS, and glutathione status.
Topics: Mice; Rats; Animals; Diazoxide; Streptozocin; Rats, Wistar; Reactive Oxygen Species; Diabetes Mellitus, Experimental; Thiobarbituric Acid Reactive Substances; Oxidative Stress; Hyperglycemia; Muscle, Skeletal; Lipids; Triglycerides; Cholesterol
PubMed: 36723797
DOI: 10.1007/s10863-023-09958-7 -
Frontiers in Endocrinology 2022Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and... (Review)
Review
Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.
Topics: Humans; Child; Hyperinsulinism; Hypoglycemia; Phosphotransferases (Phosphomutases)
PubMed: 36726472
DOI: 10.3389/fendo.2022.1102307 -
Journal of Perinatology : Official... Nov 2018Diazoxide is used to treat infants with persistent hypoglycemia, but the prevalence of its use and adverse effects are not well described. We report demographic and...
OBJECTIVE
Diazoxide is used to treat infants with persistent hypoglycemia, but the prevalence of its use and adverse effects are not well described. We report demographic and clinical characteristics of infants treated with diazoxide in neonatal intensive care units (NICUs).
STUDY DESIGN
Retrospective cohort study of infants 24-41 weeks' gestation admitted to 392 NICUs from 1997-2016, comparing characteristics between hypoglycemic infants exposed/not exposed to diazoxide. For diazoxide courses > 1 day, we report percentages of infants starting diuretics and/or developing new ventilator/oxygen requirement during therapy.
RESULTS
Among 1,249,466 infants, 185,832 had hypoglycemia; 1066/185,832 (0.57%) received diazoxide. Diazoxide use increased over time (P = 0.001). Infants receiving diazoxide varied from 0-14.9% among centers. New diuretic courses were associated with 91/664 (14%), and new oxygen or ventilator requirement during therapy was associated with 64/556 (12%) and 34/647 (5%), respectively.
CONCLUSIONS
Diazoxide use in NICU settings has increased over time. Infants receiving diazoxide commonly received diuretics.
Topics: Diazoxide; Drug Utilization; Female; Gestational Age; Humans; Hypoglycemia; Infant, Newborn; Intensive Care Units, Neonatal; Male; Prevalence; Retrospective Studies; United States
PubMed: 30206345
DOI: 10.1038/s41372-018-0218-4 -
Medicina Clinica Jun 2018
Review
Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Autoimmune Diseases; C-Peptide; Dexamethasone; Diazoxide; Diet, Diabetic; Female; Glucose; Glucose Intolerance; Humans; Hyperinsulinism; Hypoglycemia; Immunosuppressive Agents; Insulin; Liver Neoplasms; Polyethylene Glycols; Proinsulin; Sigmoid Neoplasms
PubMed: 29198580
DOI: 10.1016/j.medcli.2017.10.032 -
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 -
Reviews in Endocrine & Metabolic... Dec 2023The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses... (Review)
Review
The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses drug-related hypoglycemia, but it misses a focus on drug-induced hyperinsulinemic hypoglycemia (DHH). Here we reviewed the association existing between drugs and hyperinsulinemic hypoglycemia. We primarily selected on the main electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) the reviews on drug-induced hypoglycemia. Among the drugs listed in the reviews, we selected the ones linked to an increase in insulin secretion. For the drugs missing a clear association with insulin secretion, we investigated the putative mechanism underlying hypoglycemia referring to the original papers. Our review provides a list of the most common agents associated with hyperinsulinemic hypoglycemia (HH), in order to facilitate both the recognition and the prevention of DHH. We also collected data about the responsiveness of DHH to diazoxide or octreotide.
Topics: Humans; Hypoglycemia; Hyperinsulinism; Diazoxide; Insulin Secretion
PubMed: 37552352
DOI: 10.1007/s11154-023-09828-y -
Endocrinology, Diabetes & Metabolism... Nov 2022A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia....
SUMMARY
A 52-year-old female presented with recurrent episodes of fasting or post-absorptive hypoglycemia. A 72-h fasting test confirmed endogenous hyperinsulinemia. Conventional imaging was unremarkable. Selective pancreatic arterial calcium stimulation and hepatic venous sampling showed a maximum calcium-stimulated insulin concentration from several pancreatic areas, mainly the proximal splenic artery and the proximal gastroduodenal artery, suggesting the presence of one or more occult insulinoma(s) in the region of the pancreatic body. 68Ga-DOTA-exendin-4 PET/CT showed however generalized increased uptake in the pancreas and a diagnosis of nesidioblastosis was therefore suspected. The patient has been since successfully treated with dietetic measures and diazoxide. Treatment efficacy was confirmed by a flash glucose monitoring system with a follow-up of 7 months.
LEARNING POINTS
Adult nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia. The distinction between insulinoma and nesidioblastosis is essential since the therapeutic strategies are different. 68Ga-DOTA-exendin-4 PET/CT emerges as a new noninvasive diagnostic tool for the localization of an endogenous source of hyperinsulinemic hypoglycemia. Medical management with dietetic measures and diazoxide need to be considered as a valuable option to treat patients with adult nesidioblastosis. Flash glucose monitoring system is helpful for the evaluation of treatment efficacy.
PubMed: 36448840
DOI: 10.1530/EDM-22-0325 -
Heliyon Sep 2023Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose...
Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose oral diazoxide is beneficial for severe or recurrent transitional neonatal hypoglycaemia (the NeoGluCO Study, registration ANZCTR12620000129987). The present study aimed to develop and validate the parameters for quantifying diazoxide from neonatal plasma samples, and to assess the stability of extemporaneously prepared diazoxide suspensions to support the NeoGluCO Study. To determine the plasma concentration of diazoxide, a protein precipitation mediated extraction protocol was developed, which demonstrated >94% diazoxide extraction recoveries from all samples. The method was linear over the range of 0.2-40 μg/mL (R > 0.9994) with a limit of quantification of 0.2 μg/mL. Accuracy of the method was within 97-106% with relative standard deviation < 6% for all samples. Diazoxide-plasma samples were stable for up to three months at -20 °C and up to 48 h when stored in the auto-sampler. Samples were stable for up to two freeze-thaw cycles, with further cycles compromising stability of diazoxide in plasma. The developed method was applied to determine chemical stability of the extemporaneously prepared diazoxide suspensions. These were stable at both 2-8 °C and 25 °C/60% RH, with 98% of diazoxide remaining after 35 days in both storage conditions. Diazoxide was successfully quantified from plasma collected from six neonates enrolled in the NeoGluCO Study, using the developed protocol. Overall, an efficient and reproducible extraction protocol was developed and validated for the estimation of diazoxide from human plasma.
PubMed: 37810084
DOI: 10.1016/j.heliyon.2023.e20101