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Cardiovascular Drugs and Therapy Feb 2023Doxorubicin-induced cardiotoxicity (DIC) is a common side effect of doxorubicin chemotherapy, and a major mechanism of DIC is inflammation. However, no effective method...
PURPOSE
Doxorubicin-induced cardiotoxicity (DIC) is a common side effect of doxorubicin chemotherapy, and a major mechanism of DIC is inflammation. However, no effective method exists to prevent DIC. In the present study, we investigated the cardioprotective effects of nicorandil against DIC using multiparametric cardiac magnetic resonance (CMR) imaging and elucidated the anti-inflammatory properties of nicorandil in rat models.
METHODS
Male Sprague-Dawley rats received four weekly intraperitoneal doxorubicin doses (4 mg/kg/injection) to establish the DIC model. After treatment with or without nicorandil (3 mg/kg/day) or diazoxide (10 mg/kg/day) orally, all the groups underwent weekly CMR examinations, including cardiac function and strain assessment and T2 mapping, for 6 weeks. Additionally, blood samples and hearts were collected to examine inflammation and histopathology.
RESULTS
According to our results, the earliest DIC CMR parameter in the doxorubicin group was T2 mapping time prolongation compared with the DIC rats treated with nicorandil (doxorubicin+nicorandil group) at week 2. Subsequently, the left ventricular ejection fraction (LVEF) and global peak systolic myocardial strain in the doxorubicin group were significantly reduced, and nicorandil effectively inhibited these effects at week 6. Our results were confirmed by histopathological evaluations. Furthermore, nicorandil treatment had a protective effect against the doxorubicin-induced inflammatory response. Interestingly, similar protective results were obtained using the K channel opener diazoxide.
CONCLUSION
Collectively, our findings indicate that nicorandil application ameliorates DIC in rats with significantly higher cardiac function and myocardial strain and less fibrosis, apoptosis and inflammatory cytokine production. Nicorandil prevents T2 abnormalities in the early stages of DIC, showing a high clinical value for early nicorandil treatment in chemotherapy patients.
Topics: Rats; Male; Animals; Nicorandil; Diazoxide; Cardiotoxicity; Stroke Volume; Rats, Sprague-Dawley; Ventricular Function, Left; Doxorubicin; Magnetic Resonance Imaging; Inflammation
PubMed: 34595611
DOI: 10.1007/s10557-021-07252-5 -
Cureus Mar 2023A low blood glucose level (less than 55 mg/dL) associated with autonomic and neuroglycopenic signs and symptoms that resolve after glucose administration establishes...
A low blood glucose level (less than 55 mg/dL) associated with autonomic and neuroglycopenic signs and symptoms that resolve after glucose administration establishes Whipple's triad, indicating the presence of a hypoglycemic disorder. Insulinoma remains the most common cause of endogenous hyperinsulinemia. We present the case of a 73-year-old male who was brought to the emergency department after losing consciousness. On initial assessment, severe hypoglycemia was identified and treated. No abnormalities were detected on the physical examination, initial blood tests, abdominal ultrasound and computed tomography (CT) thorax, and abdomen and pelvis. The patient had another episode of symptomatic hypoglycemia, and the blood tests performed were compatible with endogenous hyperinsulinism. The patient was started on diazoxide to prevent further hypoglycemia episodes. Magnetic resonance imaging (MRI) showed a nodular area in the cephalic region of the pancreas, and the patient was discharged with diazoxide and flash glucose monitoring. In the follow-up appointment, he presented with signs and symptoms of congestive heart failure. Endoscopic ultrasound was requested, but the patient was at high risk for complications while undergoing the procedure under anesthesia due to congestive heart failure. A Gallium-DOTA-NOC positron emission tomography and computed tomography (PET-CT) was requested and confirmed the presence of a nodular area in the cephalic region of the pancreas. He was referred to general surgery for definitive treatment. Insulinoma is still a challenging medical condition. Therefore, management by a multidisciplinary team is essential. This case highlights the impact that side effects of medication used to treat this condition can have. Diazoxide was initiated to stop severe recurrent hypoglycemia; however, the patient developed congestive heart failure and was unable to undergo an endoscopic ultrasound to localize the lesion, resulting in a delay in diagnosis and definitive treatment. Diazoxide is a potent hyperglycemic drug but it can also cause fluid retention, nausea, hypertrichosis, neutropenia, and thrombocytopenia.
PubMed: 37123740
DOI: 10.7759/cureus.36804 -
Clinical Endocrinology Mar 2021Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin...
OBJECTIVE
Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith-Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH. This systematic review of children with HH referred to a tertiary centre aims at estimating the frequency of a syndromic/multisystem condition to help address stratification of genetic analysis in infants with HH.
METHODS
We performed a retrospective study of 69 patients with syndromic features and hypoglycaemia in a specialist centre from 2004 to 2018.
RESULTS
Biochemical investigations confirmed HH in all the cases and several genetic diagnoses were established. Responsiveness to medications and the final outcome following medical treatment or surgery were studied.
CONCLUSIONS
This study highlights the association of HH with a wide spectrum of syndromic diagnoses and that children with features suggestive of HH-associated syndromes should be monitored for hypoglycaemia. If hypoglycaemia is documented, they should also be screened for possible HH. Our data indicate that most syndromic forms of HH are diazoxide-responsive and that HH resolves over time; however, a significant percentage continues to require medications years after the onset of the disease. Early diagnosis of hyperinsulinism and initiation of treatment is important for preventing hypoglycaemic brain injury and intellectual disability.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Follow-Up Studies; Humans; Infant; Retrospective Studies; Syndrome
PubMed: 33345357
DOI: 10.1111/cen.14393 -
Angewandte Chemie (International Ed. in... Jul 2022Benzoxathiazine dioxide, as a bioisostere of the clinically widely used diazoxide, exhibits interesting biological activity. However, limited success has been achieved...
Benzoxathiazine dioxide, as a bioisostere of the clinically widely used diazoxide, exhibits interesting biological activity. However, limited success has been achieved in terms of its concise and direct synthesis. We report herein a facile electrochemical migratory cyclization of N-acylsulfonamides to access a diverse array of benzoxathiazine dioxides. The inclusion of electrochemistry is crucial for realizing such a novel transformation, which is substantiated both by the experiments and density-functional-theory calculations.
Topics: Cyclization; Electrochemistry
PubMed: 35606293
DOI: 10.1002/anie.202206058 -
Human Molecular Genetics Mar 2018Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for...
Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for FRDA available, especially for neurological deficits. In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mammalian target of rapamycin (mTOR) pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3 mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity, and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
Topics: Animals; Cell Line; Cells, Cultured; Diazoxide; Disease Models, Animal; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Proteins; Frataxin
PubMed: 29325032
DOI: 10.1093/hmg/ddy016 -
The Pan African Medical Journal 2020Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates... (Review)
Review
Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (CHI) is the most common and severe cause of persistent hypoglycemia in neonates and children, it represents a group of clinically, genetically and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic β-cells. It is extremely important to recognize this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, CHI is divided mainly into two types focal and diffuse disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localized to a small region of the pancreas. Recent discoveries of the genetic causes of CHI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a case of sever congenital hyperinsulinism in a girl admitted for lethargy, irritability and general seizures accompanied with profound hypoglycemia, in spite of aggressive medical treatment, she died because of sever congenital hyperinsulinism diazoxide unresponsive.
Topics: Congenital Hyperinsulinism; Diazoxide; Fatal Outcome; Female; Humans; Infant, Newborn; Seizures; Severity of Illness Index
PubMed: 32537058
DOI: 10.11604/pamj.2020.35.53.16604 -
The Journal of Endocrinology Jul 2021The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High...
The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism, and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment for 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any significant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits occurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic changes following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improves substrate and energy metabolism in DIO mice.
Topics: Animals; Body Composition; Diazoxide; Diet, High-Fat; Energy Metabolism; Growth Hormone; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity
PubMed: 34156345
DOI: 10.1530/JOE-20-0616 -
Frontiers in Endocrinology 2022Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in... (Review)
Review
Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in isolation, or present as a feature of syndromic disease. Establishing the underlying aetiology of the hyperinsulinism is critical for guiding medical management of this condition especially in children with diazoxide-unresponsive hyperinsulinism where the underlying genetics determines whether focal or diffuse pancreatic disease is present. Disease-causing single nucleotide variants affecting over 30 genes are known to cause persistent hyperinsulinism with mutations in the KATP channel genes ( and ) most commonly identified in children with severe persistent disease. Defects in methylation, changes in chromosome number, and large deletions and duplications disrupting multiple genes are also well described in congenital hyperinsulinism, further highlighting the genetic heterogeneity of this condition. Next-generation sequencing has revolutionised the approach to genetic testing for congenital hyperinsulinism with targeted gene panels, exome, and genome sequencing being highly sensitive methods for the analysis of multiple disease genes in a single reaction. It should though be recognised that limitations remain with next-generation sequencing with no single application able to detect all reported forms of genetic variation. This is an important consideration for hyperinsulinism genetic testing as comprehensive screening may require multiple investigations.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; KATP Channels; Mutation
PubMed: 35872984
DOI: 10.3389/fendo.2022.873254 -
Cell & Bioscience 2020Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells...
BACKGROUND
Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells and reduce Ca elevations produced by ischemia-reperfusion, protecting the heart from damage. In this study we tested the hypothesis that opening mKATP channels regulates expression of the major components of store-operated Ca entry (SOCE) STIM1 and Orai1.
RESULTS
Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot experiments showed that diazoxide increased expression of STIM1 and Orai1 at the mRNA and protein levels, respectively, in adult rat cardiomyocytes. Immunofluorescence analyses revealed that diazoxide also disrupted the striated distribution pattern of STIM1. These effects were prevented by the ROS scavenger -acetyl cysteine (NAC), the mKATP channel antagonist 5-hydroxydecanoate (5-HD), or the protein synthesis inhibitor cycloheximide (CHX). Confocal microscopy revealed that diazoxide also led to nuclear translocation of the transcription factors c-Fos and NFκB, which was also blocked by NAC or 5-HD. Finally, the MAPK pathway inhibitor UO126 attenuated diazoxide-induced upregulation of STIM1 and Orai1 expression.
CONCLUSIONS
Our results suggest that opening mitochondrial potassium ATP channels with diazoxide upregulates the expression of STIM1 and Orai1 by de novo synthesis by a mechanism that involves NFkB, c-Fos, and ROS via MAPK/ERK signaling.
PubMed: 32817784
DOI: 10.1186/s13578-020-00460-w -
ChemMedChem Apr 2021Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII...
Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition and their effect on cancer cells for the first time. A 15-fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC of 2.93±0.07 μM in a cellular model of triple-negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as-yet-undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple-negative breast cancer.
Topics: Antineoplastic Agents; Benzothiadiazines; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Halogenation; Humans; Molecular Structure; Structure-Activity Relationship
PubMed: 33331124
DOI: 10.1002/cmdc.202000729