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ERJ Open Research Nov 2023The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary... (Review)
Review
The ATP-sensitive potassium channels and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in the gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants. This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed. Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analysed data from the World Health Organization pharmacovigilance database (VigiBase). Significant disproportionality signals link diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.
PubMed: 37965230
DOI: 10.1183/23120541.00350-2023 -
Obesity (Silver Spring, Md.) Feb 2024This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi...
OBJECTIVE
This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS).
METHODS
The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety.
RESULTS
DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%).
CONCLUSIONS
DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.
Topics: Humans; Child, Preschool; Prader-Willi Syndrome; Diazoxide; Hyperphagia; Body Composition; Insulin
PubMed: 37919617
DOI: 10.1002/oby.23928 -
JCEM Case Reports Jul 2023Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy. Mutations in the gene for heterozygous hepatocyte nuclear transcription...
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy. Mutations in the gene for heterozygous hepatocyte nuclear transcription factor 4-alpha () account for approximately 5% of cases and are inherited in an autosomal dominant fashion or arise as de novo mutations. This case describes a unique presentation of parental gonadal, or germline, mosaicism as the suspected inheritance pattern for siblings with congenital hyperinsulinism caused by mutations. Two siblings presented with hypoglycemia in the first hours of life and were subsequently confirmed to have hyperinsulinism. In each patient, glycemic control was achieved at relatively low doses of diazoxide. Both siblings tested positive for the same mutation, whereas the parents tested negative for mutations. Gonadal, or germline, mosaicism became the presumed leading diagnosis, given 2 unaffected parents with 2 children with congenital hyperinsulinism. The older sibling demonstrated additional clinical features of liver disease and renal Fanconi syndrome, both of which are associated with mutations. Genetic testing plays an important role in the diagnosis and management of congenital hyperinsulinism. mutations may arise by a range of mechanisms, including gonadal, or germline, mosaicism. mutations have phenotypic variance that may affect multiple organ systems at any age.
PubMed: 37908999
DOI: 10.1210/jcemcr/luad089 -
JCEM Case Reports Mar 2023We report a 3-year-old girl with persistent hypoglycemia and hyperinsulinism secondary to -associated Kabuki syndrome (KS). During the neonatal period, the patient had...
We report a 3-year-old girl with persistent hypoglycemia and hyperinsulinism secondary to -associated Kabuki syndrome (KS). During the neonatal period, the patient had multiple complications, including gastroesophageal reflux disease, failure to thrive, G-tube dependence, congenital heart disease, and persistent hypoglycemia. The initial workup at 2 weeks of age was suggestive of hyperinsulinism. She was treated with intravenous glucose infusion and diazoxide. She was discharged from the NICU on diazoxide, chlorothiazide, and enteral feeds. Diazoxide was discontinued at 2 months old secondary to adverse effects. Hyperinsulinemic hypoglycemia was ultimately confirmed with a glucagon stimulation test at 5 months of age. At 11 months of age, when the enteral feeds were attempted to be spaced, she presented to our outpatient clinic with persistent hypoglycemia. Review of prior outside records confirmed a negative congenital hyperinsulinism genetic panel. She was treated with maltodextrin, enteral feeds, and close glucose monitoring. We noted that she had dysmorphic features that were suggestive of KS. At 2 years of age, a whole exome sequence confirmed a pathogenic mutation in . Persistent hypoglycemia beyond the neonatal period is a rare finding in KS. In addition, it is a more common finding in KS type 2 ().
PubMed: 37908464
DOI: 10.1210/jcemcr/luad032 -
JCEM Case Reports Sep 2023We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as...
We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as acetylcarnitine deficiency. A 9-year-old girl initially diagnosed with and treated for acetylcarnitine deficiency at an outside hospital presented with recurrent hypoglycemia, failure to thrive, poor weight gain, and short stature. She had discontinued levocarnitine therapy because of lack of response, and testing with us demonstrated a normal carnitine and acyl carnitine panel and hyperinsulinemic hypoglycemia during a diagnostic fast. Oral diazoxide and hydrochlorothiazide were initiated with resolution of hypoglycemia. She had iron deficiency anemia, but an upper gastrointestinal evaluation was normal. Genetic testing confirmed a diagnosis of CDG 1b caused by deficiency of mannose phosphate isomerase. Oral mannose was started with gradual reduction in and eventual discontinuation of the diazoxide dose. Hypoglycemia in the pediatric age group needs a systematic approach. It is important to raise awareness of CDG 1b, which can present as persistent hyperinsulinemic hypoglycemia. Mannose supplementation can ameliorate clinical symptoms and biochemical abnormalities.
PubMed: 37908211
DOI: 10.1210/jcemcr/luad109 -
Jornal de Pediatria 2024Congenital hyperinsulinism (CHI) is a heterogeneous genetic disease characterized by increased insulin secretion and causes persistent hypoglycemia in neonates and...
OBJECTIVE
Congenital hyperinsulinism (CHI) is a heterogeneous genetic disease characterized by increased insulin secretion and causes persistent hypoglycemia in neonates and infants due to dysregulation of insulin secretion by pancreatic β cells. Babies with severe hypoglycemia and for whom medical treatment has been ineffective usually require surgical treatment with near-total pancreatectomy. To evaluate the clinical and surgical aspects affecting survival outcomes in babies diagnosed with CHI in a single tertiary care center.
METHODS
Retrospective Cohort study involving a single university tertiary center for the treatment of CHI. The authors study the demographics, clinical, laboratory, and surgical outcomes of this casuistic.
RESULTS
61 % were female, 39 % male, Birth weight: 3576 g (±313); Age of onset of symptoms: from the 2nd hour of life to 28 days; Time between diagnosis and surgery ranged between 10 and 60 days; Medical clinical treatment, all patients received glucose solution with a continuous glucose infusion and diazoxide. 81 % of the patients used corticosteroids, 77 %. thiazide, 72 % octreotide, 27 % nifedipine; Neurological sequelae during development and growth: 54 % had some degree of delay in neuropsychomotor development, 27 % obesity. Surgery was performed open in 6 and 12 minimally invasive surgery (MIS).
HISTOPATHOLOGY
2 focal and 16 diffuse, Length of stay (days) was lower in MIS (p < 0.05). Survival was 100 %.
CONCLUSIONS
CHI is a rare and difficult-to-manage tumor that must be performed in a multidisciplinary and tertiary center. Most surgical results are good and the laparoscopic approach to disease has been the best choice for patients.
Topics: Infant; Infant, Newborn; Humans; Male; Female; Retrospective Studies; Brazil; Congenital Hyperinsulinism; Glucose; Treatment Outcome
PubMed: 37866397
DOI: 10.1016/j.jped.2023.09.005 -
The Journal of Maternal-fetal &... Dec 2023To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH).
OBJECTIVES
To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH).
METHODS
This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included.
RESULTS
A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the gene were found in four patients with CHI.
CONCLUSIONS
The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.
Topics: Infant; Infant, Newborn; Humans; Diazoxide; Retrospective Studies; Congenital Hyperinsulinism; Sirolimus; Mutation
PubMed: 37860935
DOI: 10.1080/14767058.2023.2272014 -
Pregnancy Hypertension Dec 2023Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking.
OBJECTIVE
To compare treatment success with antihypertensives and categorize by route of administration.
SEARCH STRATEGY
MEDLINE, Embase, PubMed, Web of Science, Scopus, CINAHL, and clinicaltrials.gov were searched without date restriction.
DATA COLLECTION
Peer-reviewed randomized controlled trials (RCTs) comparing pharmacologic agents used to treat hypertension in parturients were included. Evaluated treatment groups included IV-labetalol (BBIV), IV-hydralazine (DIV), oral-nifedipine (CCBPO), sublingual nifedipine (CCBSL), IV-calcium channel blocker (nonspecific)(CCBIV), IV-nitroglycerine (NTG), epoprostenol infusion (PRO), IV-ketanserin (5HT2B), IV-diazoxide (BZO), oral-nifedipine + methyldopa (CCBAG), oral-methyl-dopa (AAG), and oral prazosin (ABPO).
ANALYSIS
Seventy-four studies (8324 patients) were eligible post PRISMA guidelines screening. Results were pooled using a Bayesian-approach for success of treatment (study defined target blood pressure), time to achieve target pressure, and neonatal intensive-care admissions.
RESULTS
Treatment success (primary outcome, 55 trials with 5518 patients) was analyzed. Surface under the cumulative ranking curve (SUCRA) was categorized for 13 drugs, CCBPO (0.84) followed by CCBSL (0.78) were most likely to be effective in achieving target blood pressure. After sub-grouping by presence/absence of preeclampsia, CCB-PO ranked highest for both [(0.82) vs. (0.77), respectively]. Serotonin antagonists (0.99) and nitroglycerin (0.88) ranked highest for time to target pressure. NICU admissions were lowest for alpha-2 agonists (0.89), followed by BB PO (0.82) and hydralazine IV (0.49).
CONCLUSION
Oral calcium-channel blockers ranked highest for treatment success. Ketanserin achieved target blood pressure fastest, warranting additional research. The results should be interpreted with caution as SUCRA values may not indicate whether the differences between interventions have clinically meaningful effect sizes.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Antihypertensive Agents; Calcium Channel Blockers; Hydralazine; Hypertension; Ketanserin; Methyldopa; Network Meta-Analysis; Nifedipine; Pre-Eclampsia; Randomized Controlled Trials as Topic
PubMed: 37857042
DOI: 10.1016/j.preghy.2023.10.005 -
Internal Medicine (Tokyo, Japan) May 2024We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with end-stage renal disease...
We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with end-stage renal disease (ESRD). A 50-year-old man with ESRD and a history of gastrectomy underwent hemodialysis. Although he was administered voglibose to treat recurrent reactive hypoglycemia caused by late dumping syndrome, he had difficulty continuing treatment because of gastrointestinal side effects. When he began diazoxide treatment, the reactive hypoglycemia improved. The dose was gradually increased with no apparent side effects, and the hypoglycemic attacks disappeared one year after the start of treatment.
Topics: Humans; Diazoxide; Male; Middle Aged; Hypoglycemia; Kidney Failure, Chronic; Gastrectomy; Dumping Syndrome; Treatment Outcome; Renal Dialysis
PubMed: 37813619
DOI: 10.2169/internalmedicine.1704-23 -
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