Dasiglucagon in Children with Congenital Hyperinsulinism up to 1 Year of Age: Results from a Randomized Clinical Trial.

Context: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia in childhood with considerable risk of lifelong neurological sequelae. Available pharmacological therapies are limited. Dasiglucagon is a glucagon analog for the treatment of hypoglycemia.

Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children.

Context: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI.

Objective: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC).

Novel peptide calcitonin gene-related peptide antagonists for migraine therapy.

Objectives: It has previously been shown that the peptide (34Pro,35Phe)CGRP27-37 is a potent calcitonin gene-related peptide, CGRP receptor antagonist, and in this project we aimed to improve the antagonist potency through the structural modification of truncated C-terminal CGRP peptides.

Methods: Six peptide analogues were synthesized and the anti-CGRP activity confirmed using both in vitro and in vivo studies.

Key Findings: A 10 amino acid-containing peptide VPTDVGPFAF-NH2 (P006) was identified as a key candidate to take forward for in vivo evaluation, where it was shown to be an effective antagonist after intraperitoneal injection into mice.

The development and optimisation of an HPLC-based in vitro serum stability assay for a calcitonin gene-related peptide receptor antagonist peptide.

Evaluation of the stability of peptide drug candidates in biological fluids, such as blood serum, is of high importance during the lead optimisation phase. Here, we describe the optimisation and validation of a method for the evaluation of the stability of a lead calcitonin gene-related peptide antagonist peptide (P006) in blood serum. After initially determining appropriate peptide and human serum concentrations and selection of the quenching reagent, the HPLC method optimisation used two experimental designs, Plackett-Burman design and Taguchi design.

Development of a novel cell-based, In-Cell Western/ERK assay system for the high-throughput screening of agonists acting on the delta-opioid receptor.

Extracellular signal-regulated kinases (ERKs) are important signaling mediators in mammalian cells and, as a result, one of the major areas of research focus. The detection and quantification of ERK phosphorylation as an index of activation is normally conducted using immunoblotting, which does not allow high-throughput drug screening. Plate-based immunocytochemical assays provide a cheaper and relatively high-throughput alternative method for quantifying ERK phosphorylation.

Planning experiments: Updated guidance on experimental design and analysis and their reporting III.

Scientists who plan to publish in British Journal of Pharmacology (BJP) must read this article before undertaking a study. This editorial provides guidance for the design of experiments. We have published previously two guidance documents on experimental design and analysis (Curtis et al.

Dasiglucagon demonstrates reduced costs in the treatment of severe hypoglycemia in a budget impact model.

Approximately 7.3 million people with type 1 or type 2 diabetes (T1D/T2D) are treated with insulin, placing them at higher risk of severe hypoglycemia (SH). SH requires assistance of another individual and often necessitates the prompt administration of intravenous glucose, injectable glucagon, or both.

Congenital hyperinsulinism in infancy and childhood: challenges, unmet needs and the perspective of patients and families.

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children, and carries a considerable risk of neurological damage and developmental delays if diagnosis and treatment are delayed. Despite rapid advances in diagnosis and management, long-term developmental outcomes have not significantly improved in the past years. CHI remains a disease that is associated with significant morbidity, and psychosocial and financial burden for affected families, especially concerning the need for constant blood glucose monitoring throughout patients' lives.

A Comparative Study of Dasiglucagon Ready-to-Use Autoinjector and Glucagon Emergency Kit During Rescue from Simulated Severe Hypoglycemia.

Severe hypoglycemic episodes are life-threatening events demanding rapid administration of glucagon by a caregiver or bystander. The glucagon analog dasiglucagon is stable in aqueous formulation and therefore suitable for delivery in a ready-to-use autoinjector, potentially increasing speed and ease of use compared with standard glucagon emergency kits (GEKs). In an open label, randomized, crossover, comparative device handling study, trained caregivers and untrained bystanders administered the dasiglucagon autoinjector or Eli Lilly GEK to manikins in a simulated emergency hypoglycemia situation.

A pilot of the feasibility and usefulness of an aged obese model for use in stroke research.

Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers.

RESULTS OF A 24-WEEK TRIAL OF TECHNOSPHERE INSULIN VERSUS INSULIN ASPART IN TYPE 2 DIABETES.

Objective: To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes.

Methods: This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.

Understanding inhaled Technosphere Insulin: Results of an early randomized trial in type 1 diabetes mellitus.

Background: Technosphere Insulin (TI) is an inhaled insulin. Studies comparing TI with short-acting insulin analogues provide important insights on efficacy, dosing, and time course of action.

Methods: Planned enrollment of 230 subjects was limited to 138 due to premature study discontinuation.

Comprehensive Pulmonary Safety Review of Inhaled Technosphere Insulin in Patients with Diabetes Mellitus.

Background And Objective: Technosphere Insulin (TI), a human insulin powder for inhalation (Afrezza; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety.

Methods: Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies.

A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine.

Objectives: To investigate the formulation of the peptide-based antagonist ( Pro, Phe)CGRP , of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment.

Methods: Peptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC-MS.

A Novel G Protein-Biased Agonist at the Opioid Receptor with Analgesic Efficacy in Models of Chronic Pain.

Agonists at the opioid receptor are known to be potent antihyperalgesics in chronic pain models and effective in models of anxiety and depression. However, some opioid agonists have proconvulsant properties while tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the opioid receptor differentially engage signaling and regulatory pathways with significant effects on behavioral outcomes.

Sex-specific hippocampal metabolic signatures at the onset of systemic inflammation with lipopolysaccharide in the APPswe/PS1dE9 mouse model of Alzheimer's disease.

Systemic inflammation enhances the risk and progression of Alzheimer's disease (AD). Lipopolysaccharide (LPS), a potent pro-inflammatory endotoxin produced by the gut, is found in excess levels in AD where it associates with neurological hallmarks of pathology. Sex differences in susceptibility to inflammation and AD progression have been reported, but how this impacts on LPS responses remains under investigated.

A multinational observational study assessing insulin use: Understanding the determinants associated with progression of therapy.

Aims: To describe global patterns of insulin treatment and to assess the impact of patient, provider, health system and economic influences on treatment decisions for patients with insulin-treated type 2 diabetes (T2D).

Methods: This prospective cohort study of insulin-treated patients with T2D was conducted across 18 countries categorized as high, upper-middle or lower-middle income regions. Information collected from patients included knowledge of diabetes, experiences and interactions with their healthcare provider.

Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse.

Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1-knock out mice.

Identifying insulin treatment responders with a composite measure: beyond Hba1c < 7% in patients with type 2 diabetes.

Objectives: Many insulin-treated patients with type 2 diabetes (T2D) do not reach hemoglobin A1c (HbA1c) < 7%, but have clinically relevant HbA1c reductions. Using an integrated database (IDB) of 53 insulin lispro clinical trials and a real-world evidence (RWE) database of T2D patients initiating insulin therapy, an expanded HbA1c measure was used to identify responders to insulin therapy.

Methods: Analysis included 4,908 patients (IDB) and 1,134 patients (RWE) with T2D treated with any insulin regimen with a baseline and ≥1 post-baseline HbA1c.

Functional Selectivity at Cannabinoid Receptors.

It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred to as functional selectivity (also known as agonist-directed trafficking, ligand-induced differential signaling, or biased agonism). It is important because even small structural differences can result in significant variations in overall agonist effects (wanted and unwanted) depending on which postreceptor signaling systems are engaged by each agonist/receptor pairing.