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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 -
Archives of Disease in Childhood Sep 2023
Topics: Female; Infant, Newborn; Humans; Diazoxide; Enterocolitis, Necrotizing; Hypoglycemia; Infant, Newborn, Diseases; Fetal Diseases
PubMed: 37369382
DOI: 10.1136/archdischild-2023-325726 -
Diabetes Sep 2023Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can...
UNLABELLED
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.
ARTICLE HIGHLIGHTS
Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
Topics: Animals; Mice; Antibodies; Blood Glucose; Congenital Hyperinsulinism; Diazoxide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperinsulinism; Mutation; Sulfonylurea Receptors
PubMed: 37358194
DOI: 10.2337/db22-1039 -
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 -
Alcohol (Fayetteville, N.Y.) Dec 2023The leukotrienes, lipid mediators, have a role in gastric damage induced by ethanol. Here, the gastroprotective effect of montelukast, an antagonist of the leukotriene...
The leukotrienes, lipid mediators, have a role in gastric damage induced by ethanol. Here, the gastroprotective effect of montelukast, an antagonist of the leukotriene receptor, and the involvement of the NO-cGMP-K channel pathway, were evaluated in gastric damage induced by ethanol in rats. For this, l-arginine, l-NAME, methylene blue (guanylate cyclase inhibitor), sildenafil, diazoxide, or glibenclamide (ATP-sensitive potassium channel blocker) were administered 30 min before montelukast (0.1, 1, 10, and 20 mg/kg, by mouth [p.o.]). After 1 h, to induce gastric damage, the rats received absolute ethanol (4 mL/kg, p.o.), and then microscopic, macroscopic, and pro-inflammatory parameters (TNF-α and IL-1β) were assessed. Results obtained here revealed that montelukast significantly attenuated the macroscopic and microscopic lesions induced by ethanol. Montelukast also reduced IL-1β and TNF-α levels. It was also observed that NOS inhibitor (l-NAME), methylene blue, and glibenclamide inhibited the effects of montelukast in the stomach. Moreover, the NO precursor (l-arginine), the PDE-5 inhibitor (sildenafil), and a potassium channel opener (diazoxide) before montelukast produced gastroprotective effects. In conclusion, the effect of montelukast against gastric lesions induced by ethanol is mediated, at least in part, through the pathway of the NO-cGMP-K channel.
Topics: Rats; Animals; NG-Nitroarginine Methyl Ester; Nitric Oxide; Sildenafil Citrate; Methylene Blue; Ethanol; Cyclic GMP; Glyburide; Tumor Necrosis Factor-alpha; Diazoxide; KATP Channels; Stomach; Arginine; Adenosine Triphosphate
PubMed: 37295565
DOI: 10.1016/j.alcohol.2023.05.008 -
Journal of Pediatric Endocrinology &... Aug 2023CHI is a relevant cause of persistent and severe hypoglycemia and the ABCC8 gene mutation is one of most common cause of the disease. Two main types of CHI have been...
OBJECTIVES
CHI is a relevant cause of persistent and severe hypoglycemia and the ABCC8 gene mutation is one of most common cause of the disease. Two main types of CHI have been described, diffuse and focal form. Octreotide is a medication utilized in case of diazoxide-unresponsive forms of CHI. For those CHI focal forms where is decided either to manage medically or until resolutive surgery is completed, octreotide can be administered as subcutaneous injection or as continuous subcutaneous infusion via insulin pump. However, it is unclear how to adjust the drug's daily basal pattern when a pump is used.
CASE PRESENTATION
We present a case of an infant with a diazoxide-unresponsive focal form of CHI, due to ABCC8 mutation ABCC8, treated with octreotide. To better evaluate the glycemic trend, a CGM was placed. In order to achieve a better personalization of the therapy we utilized an insulin pump for octreotide administration.
CONCLUSIONS
The adoption of the CGM and insulin pump, allowed a better personalization of the therapy and a reduction of acute carbohydrate intake, promoting a good auxological growth before resolutive surgery. What is new? Octreotide administered with an insulin pump in patient with CHI allows a wide modulation of the daily therapy. The CGM allows a continuous and a less painful control of the glycemic trend in a patient with CHI. Different basal rates, given via insulin pump may allow a better personalization of the therapy. Prevention of hypoglycemia reduces the acute introduction of carbohydrates, promoting normal growth..
Topics: Humans; Male; Infant; Congenital Hyperinsulinism; Diazoxide; Octreotide; Blood Glucose Self-Monitoring; Treatment Outcome; Insulin
PubMed: 37248699
DOI: 10.1515/jpem-2022-0643 -
Pediatrics and Neonatology Sep 2023
Topics: Humans; Infant; Diazoxide; Trichlormethiazide; Trisomy 13 Syndrome; Body Water; Treatment Outcome
PubMed: 37225554
DOI: 10.1016/j.pedneo.2023.04.003 -
Applied Biochemistry and Biotechnology Aug 2023Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis...
Islet transplantation offers improved glycemic control in individuals with type 1 diabetes mellitus. However, in vitro islet culture is associated with islet apoptosis and eventually will lose their functionality prior to transplantation. In this study, we examined the effects of mesenchymal stem cells (MSCs) secretome preconditioned with diazoxide (DZ) and trimetazidine (TMZ) on rat islet cells during pre-transplant culture. With and without preconditioned hAD-MSCs' concentrated conditioned media (CCM) were added to the culture medium containing rat islets every 12 h for 24 and 48 h, after testing for selected cytokine concentrations (interleukin (IL)-4, IL-6, IL-13). Insulin content, glucose-stimulated insulin secretion, islet cell apoptosis, and mRNA expression of pro-apoptotic (BAX, BAK-1, and PUMA) and anti-apoptotic factors (BCL-2, BCL-xL, and XIAP) in rat islets were assessed after 24 and 48 h of culture. The protein level of IL-6 and IL-4 was significantly higher in TMZ-MSC-CM compared to MSC-non-CM. In rat isolated islets, normalized secreted insulin in the presence of 16.7 mM glucose was significantly higher in treated islet groups compared to control islets at both 24 and 48 h cultivation. Also, the percentage of apoptotic islet cells TMZ-MSC-CCM-treated islets was significantly lower compared to MSC-CM and MSC-CCM-treated islets in both 24 and 48 h cultivation. Consistent with the number of apoptotic cells, after 24 h culture, the expression of BCL-2 and BCL-xL genes in the control islets was lower than all treatment islet groups and in 48 h was lower than only TMZ-MSC-CM-treated islets. Also, the expression of the XIAP gene in control islets was significantly lower compared to the TMZ-MSC-CCM-treated islets at both at 24 and 48 h. In addition, mRNA level of the BAX gene in TMZ-MSC-CCM-treated islets was significantly lower compared to other groups at 48 h. Our findings revealed that TMZ proved to be more effective than DZ and could enhance the potential of hAD-MSCs-CM to improve the function and viability of islets prior to transplantation.
Topics: Rats; Animals; Trimetazidine; Interleukin-6; Secretome; bcl-2-Associated X Protein; Islets of Langerhans; Insulin; Mesenchymal Stem Cells; Diazoxide; Glucose
PubMed: 37184724
DOI: 10.1007/s12010-023-04532-8 -
American Journal of Perinatology May 2024This study aimed to evaluate the prevalence of adverse outcomes, specifically pulmonary hypertension (PH) and suspected or confirmed necrotizing enterocolitis (NEC),...
OBJECTIVE
This study aimed to evaluate the prevalence of adverse outcomes, specifically pulmonary hypertension (PH) and suspected or confirmed necrotizing enterocolitis (NEC), and their associated risk factors, in neonates treated with diazoxide.
STUDY DESIGN
A retrospective study in infants born ≥ 31 weeks and admitted between January 2014 and June 2020. Combined adverse outcomes possibly associated to diazoxide were PH (systolic pulmonary pressure of ≥40 mm Hg or an eccentricity index ≥1.3) and suspected or confirmed NEC (suspected: stop feeds and antibiotics and confirmed: modified Bell stage ≥2). Echocardiography data extractors were masked to infants' characteristics.
RESULTS
A total of 63 infants were included; 7 (11%) with suspected and 1 (2%) with confirmed NEC. Of the 36 infants with an available echocardiography after initiation of diazoxide treatment, 12 (33%) had PH. All infants with suspected or confirmed NEC were males ( = 0.01), whereas PH occurred mostly in females (75%, = 0.02). The combined adverse outcome occurred in 14/26 (54%) infants exposed to >10 mg/kg/day, compared to 6/37 (16%) exposed to ≤10 mg/kg/day ( = 0.006). This association remained significant after adjustment for sex, small for gestational age status, and gestational age at birth (odds ratio: 6.1, 95% confidence interval: 1.7-21.7, = 0.005). Left ventricular dysfunction was found in 19 infants (30%) but was not discriminative for the combined outcome.
CONCLUSION
PH and suspected or confirmed NEC were identified frequently in neonates treated with diazoxide. A total dose >10 mg/kg/day was associated with an increased occurrence of these complications.
KEY POINTS
· PH and suspected or confirmed NEC were frequently found in neonates treated with diazoxide.. · A total dose >10 mg/kg/day was associated with an increased occurrence of these complications.. · Echocardiography screening should be considered in neonates exposed to diazoxide..
Topics: Humans; Diazoxide; Female; Infant, Newborn; Male; Enterocolitis, Necrotizing; Retrospective Studies; Hypertension, Pulmonary; Echocardiography; Risk Factors; Infant, Premature; Vasodilator Agents
PubMed: 36882098
DOI: 10.1055/s-0043-1764385 -
Annals of Pediatric Endocrinology &... Dec 2023
PubMed: 35798301
DOI: 10.6065/apem.2244068.034