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Expert Opinion on Pharmacotherapy 2023The severity of positive symptoms in schizophrenia is associated with poor prognosis. About one-third of schizophrenia patients partially respond to treatment with... (Review)
Review
INTRODUCTION
The severity of positive symptoms in schizophrenia is associated with poor prognosis. About one-third of schizophrenia patients partially respond to treatment with available antipsychotics. The purpose of the present manuscript is to provide an updated overview of novel pharmacotherapy targeting positive symptoms in schizophrenia.
AREAS COVERED
A comprehensive research on the main database sources (PubMed, PsychINFO, Isi Web of Knowledge, MEDLINE, and EMBASE) was performed to obtain original articles published till 31 January 2023 about new pharmacological strategies for the treatment of positive symptoms in schizophrenia.
EXPERT OPINION
The most promising compounds include: lamotrigine, pro-cognitive-compounds (donepezil - in the short term, idazoxan and piracetam) and drugs acting partially or totally outside the Central Nervous System (CNS) (anti-inflammatory drugs: celecoxib, methotrexate; cardiovascular compounds: L-theanine, mononitrate isosorbide, propentofylline, sodium nitroprusside; metabolic regulators: diazoxide, allopurinol; others: bexarotene, raloxifene [in women]). The effectiveness of the latter compounds indicates that other biological systems, such as immunity or metabolism can be object of future research to identify pharmacological targets for positive symptoms of schizophrenia. Mirtazapine could be useful for treating negative symptoms without increasing the risk of a worsening of delusions/hallucinations. Nevertheless, the lack of replication of studies prevents to draw definitive conclusions and future studies are needed to confirm the findings presented in this overview.
Topics: Humans; Female; Schizophrenia; Antipsychotic Agents
PubMed: 37401388
DOI: 10.1080/14656566.2023.2231346 -
PloS One 2021Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This... (Meta-Analysis)
Meta-Analysis
Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This systemic review and meta-analysis aimed to investigate the efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia (HH). The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases. The findings were summarized, and the pooled effect size and its 95% confidence interval (CI) were calculated. A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria. Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71% (95% CI 50%-93%, Pheterogeneity< 0.001, I2 = 98.3%, Peffect< 0.001). The common side effects were hypertrichosis (45%), fluid retention (20%), gastrointestinal reaction (13%), edema (11%), and neutropenia (9%). Other adverse events included pulmonary hypertension (2%) and thrombocytopenia (2%). This meta-analysis suggested that diazoxide was potentially useful in HH management; however, it had some side effects, which needed careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence.
Topics: Antihypertensive Agents; Diazoxide; Humans; Hyperinsulinism; Hypertrichosis; Hypoglycemia; Treatment Outcome; Vasodilator Agents
PubMed: 33571197
DOI: 10.1371/journal.pone.0246463 -
Frontiers in Endocrinology 2022Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and... (Review)
Review
Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of β- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI.
Topics: Biology; Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; Ligands; Receptors, Somatostatin; Somatostatin
PubMed: 36237195
DOI: 10.3389/fendo.2022.921357 -
European Journal of Pediatrics Aug 2019Hyperinsulinaemic hypoglycaemia (HH) is a major cause of hypoglycaemia in the neonatal period, infancy and childhood. It is caused by unsuppressed insulin secretion in... (Review)
Review
Hyperinsulinaemic hypoglycaemia (HH) is a major cause of hypoglycaemia in the neonatal period, infancy and childhood. It is caused by unsuppressed insulin secretion in the setting of hypoglycaemia and carries a high risk of significant neurological sequelae, such as cognitive impairment. Genetic mutations have been implicated in the pathogenesis of the condition. Other causes include intra-uterine growth retardation, perinatal asphyxia, maternal diabetes mellitus and syndromes, such as Beckwith-Wiedemann. Based on the aetiology, the clinical presentation can range from absence of symptoms to the typical adrenergic symptoms and coma and even death. The diagnosis is based on biochemical findings and the gold-standard imaging technique is 18F-DOPA PET/CT scanning. Treatment options involve medications, such as diazoxide, nifedipine, glucagon and octreotide, as well as surgery. Novel treatment, such as long-acting octreotide, lanreotide and sirolimus, may be used as an alternative to pancreatectomy. Potential future medical treatments include exendin, a GLP-1 receptor antagonist, and glucagon infusion via a pump.Conclusion: Advances in the fields of genetic testing, imaging techniques and medical treatment are beginning to provide novel insights into earlier detection, less invasive treatment approaches and fewer complications associated with the complex entity of hyperinsulinaemic hypoglycaemia. What is Known: • HH is caused by dysregulated insulin release from the β cell due to genetic mutations and carries a risk for complications, such as neurocognitive impairment. 18F-DOPA PET/CT scanning is presented as the gold-standard imaging technique currently in children with hyperinsulinaemic hypoglycaemia. • Clinical presentation is heterogeneous and treatment options include medical therapy and pancreatectomy. What is New: • 18F-DOPA PET/CT is indicated in suspected focal CHI due to paternal transmitted mutations in ABCC8 or KCNJ11. • Novel treatment options have been introduced, such as long-acting octreotide, lanreotide, sirolimus and selective nonpeptide somatostatin receptor subtype 5 (SSTR5) agonists. Future medical treatments include exendin, a GLP-1 antagonist, and glucagon infusion via a pump. However, all these options are off-label at present.
Topics: Child; Child, Preschool; Combined Modality Therapy; Congenital Hyperinsulinism; Genetic Markers; Genetic Testing; Humans; Infant; Infant, Newborn
PubMed: 31243576
DOI: 10.1007/s00431-019-03414-8 -
Tuberculosis Research and Treatment 2020There is an urgent need for better and safer therapeutic interventions for tuberculosis (TB). We assessed the effects of FDA-approved ion transport modulators, namely,...
There is an urgent need for better and safer therapeutic interventions for tuberculosis (TB). We assessed the effects of FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide (HCTZ), metformin, omeprazole, pantoprazole, phenytoin, verapamil, and drug X and Y on the growth of free and intracellular BCG. Free and intracellular BCG were cultured in the presence or absence of the test drugs for 3 to 9 days and then quantified. For both free and intracellular bacteria, cultures that were exposed to furosemide, phenytoin, or drug Y yielded lower bacteria counts compared to drug-free controls ( < 0.05). The same was observed with diazoxide, HCTZ, verapamil, and drug X, but only for intracellular BCG ( < 0.05). To assess the effects of the drugs on bactericidal activity of rifampicin, free and intracellular BCG were treated with rifampicin alone or in combination with each of the thirteen test drugs for 3 to 9 days. For extracellular bacteria, higher bacteria clearance rates were observed in cultures exposed to rifampicin in combination with amiloride HCl, diazoxide, digoxin, furosemide, HCTZ, metformin, pantoprazole, phenytoin, drug X, or drug Y than those exposed to rifampicin alone, indicating that rifampicin had a synergistic effect with these test drugs. Rifampicin was also synergistic with ambroxol HCl, diazoxide, digoxin, furosemide, HCTZ, omeprazole, pantoprazole, phenytoin, verapamil, and drug X against intracellular BCG. The antimycobacterial properties exhibited by the ion transport modulators in this study make them viable candidates as adjuncts to the current anti-TB regimens.
PubMed: 33294223
DOI: 10.1155/2020/3767915 -
Expert Review of Cardiovascular Therapy Feb 2022The role of chronic inflammatory process in the pathogenesis or exacerbation of hypertension has been already acknowledged. (Review)
Review
INTRODUCTION
The role of chronic inflammatory process in the pathogenesis or exacerbation of hypertension has been already acknowledged.
AREAS COVERED
Therefore, one can speculate that hypotensive drugs may exert some of their therapeutic effects due to immunomodulatory properties. So far, this assumption has been tested in different studies, and the resulting knowledge is summarized in the current review article that is dedicated to different groups of antihypertensives, namely calcium channel blockers, beta blockers, as well as other less commonly used medications, such as hydralazine, alfa-2 receptor agonists, diazoxide, doxazosin, aliskiren, and sodium nitroprusside. Articles were found in the Pubmed by entering the name of a specific drug/group of drugs with the words: immunology, cellular response, humoral response, inflammation, interleukin. The 2000-2021 range was used to search for all drugs except propranolol (1980-2021) and calcium blockers (1990-2021).
EXPERT OPINION
Observed decrease in serum/plasma concentration of proinflammatory cytokines, and CRP along with lower expression of adhesion molecules on immune cells strongly suggest that these drugs possess immunomodulatory properties, which seems to be crucial in the medical practice, especially in the therapy of hypertensive patients with other accompanying inflammatory-based diseases, such as type II diabetes, developed metabolic syndrome, allergies or autoimmunity.
Topics: Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Digitalis Glycosides; Humans; Hypertension
PubMed: 35130796
DOI: 10.1080/14779072.2022.2039627 -
Journal of the American Heart... Dec 2022Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of... (Review)
Review
Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; =0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; =0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; <0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (<0.01) and maximum change in ventricular pressure during isovolumetric contraction (<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.
Topics: Swine; Animals; Diazoxide; Myocardial Stunning; KATP Channels; Stroke Volume; Ventricular Function, Left; Ischemia; Myocardial Ischemia; Adenosine Triphosphate
PubMed: 36444837
DOI: 10.1161/JAHA.122.026304 -
Therapeutic Advances in Drug Safety 2021The most common cause of persistent hypoglycemia in infancy is hyperinsulinemic hypoglycemia. When conservative measures fail, providers often use medications to treat...
BACKGROUND
The most common cause of persistent hypoglycemia in infancy is hyperinsulinemic hypoglycemia. When conservative measures fail, providers often use medications to treat persistent hypoglycemia. Diazoxide is first-line therapy for neonatal hypoglycemia and works by inhibiting insulin secretion. Diazoxide is associated with fluid retention, and less commonly with respiratory decompensation and pulmonary hypertension. Case reports documenting these severe adverse events exist in the literature, although the overall incidence, risk factors, and timing for these effects in a newborn are not clearly defined.
METHODS
We performed a retrospective chart review of all infants admitted to the neonatal intensive care unit (NICU) at Regional One Health from 1 January 2013 until 15 August 2019, who received diazoxide as a treatment for persistent hypoglycemia secondary to hyperinsulinism. Patients were stratified as either having no adverse event or having an adverse outcome to the medication. A severe adverse outcome was defined as any known major side effect of the medication, which a patient developed within 2 weeks of medication initiation that led to medication discontinuation.
RESULTS
From our pharmacy database, we identified a total of 15 babies who received diazoxide for persistent hypoglycemia. Of these patients, eight (53%) were classified as having a complication requiring discontinuation of the medication. Six out of eight patients required intubation with mechanical ventilation and five out of eight patients developed pulmonary hypertension. All patients returned to their baseline respiratory support after drug discontinuation.
CONCLUSIONS
A total of 53% of our study population had an adverse outcome to diazoxide. Previous studies suggest 5% of patients may have respiratory decompensation and require ventilatory support while on diazoxide; however, 40% of our patients deteriorated and then required mechanical ventilation. Based on our data, respiratory deterioration may be more likely to occur when diazoxide is used in preterm infants, those with lower birth weight and intrauterine growth restriction.
PLAIN LANGUAGE SUMMARY
Newborns could experience a transient period of low blood glucose levels soon after birth. However, some may progress to persistent low blood glucose levels that cannot be controlled with adequate glucose infusion and may require other ways of treatment. Diazoxide is the first-line drug approved by the US Food and Drug Administration (FDA) for this condition. However, certain cases have reported the development of respiratory deterioration, including increased blood pressure in lung circulation after its use. This prompted a black box warning in 2015 by the FDA. The incidence of neonatal low blood glucose levels seems to have increased and so has the use of this drug. Our study identifies 15 newborns who received diazoxide at Regional One Health neonatal intensive care unit in the past 6 years and reports a significantly higher rate of adverse events in our population leading to drug discontinuation in almost 53% of our cases.
PubMed: 34046157
DOI: 10.1177/20420986211011338 -
BioRxiv : the Preprint Server For... Aug 2023Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed,...
OBJECTIVE
Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed, and hypoglycemic conditions, yet metabolic regulation of α-cells remains poorly understood. Here, we identified a previously unexplored role for physiological levels of leucine, which is classically regarded as a β-cell fuel, in the intrinsic regulation of α-cell glucagon release.
METHODS
GcgCre:CAMPER and GcgCre:GCaMP6s mice were generated to perform dynamic, high-throughput functional measurements of α-cell cAMP and Ca within the intact islet. Islet perifusion assays were used for simultaneous, time-resolved measurements of glucagon and insulin release from mouse and human islets. The effects of leucine were compared with glucose and the mitochondrial fuels 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH, non-metabolized leucine analog that activates glutamate dehydrogenase), α-ketoisocaproate (KIC, leucine metabolite), and methyl-succinate (complex II fuel). CYN154806 (Sstr2 antagonist), diazoxide (K activator, which prevents Ca-dependent exocytosis from α, β, and δ-cells), and dispersed α-cells were used to inhibit islet paracrine signaling and identify α-cell intrinsic effects.
RESULTS
Mimicking the effect of glucose, leucine strongly suppressed amino acid-stimulated glucagon secretion. Mechanistically, leucine dose-dependently reduced α-cell cAMP at physiological concentrations, with an IC of 57, 440, and 1162 μM at 2, 6, and 10 mM glucose, without affecting α-cell Ca. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonist or diazoxide, as well as dispersed α-cells, indicating an α-cell intrinsic effect. The effect of leucine was matched by KIC and the glutamate dehydrogenase activator BCH, but not methyl-succinate, indicating a dependence on mitochondrial anaplerosis. Glucose, which stimulates anaplerosis via pyruvate carboxylase, had the same suppressive effect on α-cell cAMP but with lower potency. Similarly to mouse islets, leucine suppressed glucagon secretion from human islets under hypoglycemic conditions.
CONCLUSIONS
These findings highlight an important role for physiological levels of leucine in the metabolic regulation of α-cell cAMP and glucagon secretion. Leucine functions primarily through an α-cell intrinsic effect that is dependent on glutamate dehydrogenase, in addition to the well-established α-cell regulation by β/δ-cell paracrine signaling. Our results suggest that mitochondrial anaplerosis-cataplerosis facilitates the glucagonostatic effect of both leucine and glucose, which cooperatively suppress α-cell tone by reducing cAMP.
PubMed: 37577685
DOI: 10.1101/2023.07.31.551113 -
Gene Aug 2023The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in...
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding K channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.
Topics: Humans; Infant; Male; Congenital Hyperinsulinism; Diazoxide; Heterozygote; Insulin; Mutation; Sulfonylurea Receptors
PubMed: 37336273
DOI: 10.1016/j.gene.2023.147576