Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial.

BACKGROUND: Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease. Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws. METHODS/DESIGN: The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada-wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) ≥ 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and "viral induced wheeze" phenotype (Fig. 1). DISCUSSION: If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication. TRIAL REGISTRATION: NCTO1429415 , registered 2 September 2011.

Pediatric constipation in the emergency department: evaluation, treatment, and outcomes.

OBJECTIVES: Limited knowledge exists surrounding the pharmacologic management of pediatric constipation in the emergency department (ED) setting and the success of interventions. Our primary objective was to determine whether enema administration is associated with 7-day ED revisits for persistent symptoms. Secondary objectives focused on assessing other predictors of ED revisits. METHODS: We conducted a retrospective cohort study of children <18 years old, diagnosed as having constipation (International Classification of Diseases-10 codes F98.1 nonorganic encopresis, K59.0 constipation) in a pediatric ED in Toronto, Canada, between November 2008 and October 2010. RESULTS: A total of 3592 visits were included; 6% (n = 225) were associated with a revisit. Children with revisits more frequently had vomiting (28% vs 17%, P = 0.001), more pain (5.7 ±â€Š3.6 vs 4.6-3.6 of 10, P = 0.01), and underwent more blood tests (19% 05, 11%, 95% confidence interval [CI] of the difference 3%-14%] and diagnostic imaging (62% vs 47%, 95% CI of the difference 9%-22%). Children administered an enema were 1.54 times more likely to revisit the ED than those who did not receive an enema (8.6% vs 5.5%, 95% CI of the difference 1.1%-5.2%, P = 0.001). Type of enema administered varied by age (P < 0.001). Regression analysis identified the following independent predictors of revisits: diagnostic imaging (odds ratio [OR] 1.54, 95% CI 1.15-2.06), vomiting (OR 1.45, 95% CI 1.07-1.98), enema administration (OR 1.40, 95% CI 1.05-1.88), and significant medical history (OR 1.26, 95% CI 1.04-1.53). CONCLUSIONS: Enema administration and diagnostic imaging are associated with revisits in children diagnosed with constipation. Their role in the ED management of pediatric constipation requires further evaluation.

Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons.

Apolipoprotein E4 (apoE4), the major genetic risk factor for late onset Alzheimer disease, assumes a pathological conformation, intramolecular domain interaction. ApoE4 domain interaction mediates the detrimental effects of apoE4, including decreased mitochondrial cytochrome c oxidase subunit 1 levels, reduced mitochondrial motility, and reduced neurite outgrowth in vitro. Mutant apoE4 (apoE4-R61T) lacks domain interaction, behaves like apoE3, and does not cause detrimental effects. To identify small molecules that inhibit domain interaction (i.e. structure correctors) and reverse the apoE4 detrimental effects, we established a high throughput cell-based FRET primary assay that determines apoE4 domain interaction and secondary cell- and function-based assays. Screening a ChemBridge library with the FRET assay identified CB9032258 (a phthalazinone derivative), which inhibits domain interaction in neuronal cells. In secondary functional assays, CB9032258 restored mitochondrial cytochrome c oxidase subunit 1 levels and rescued impairments of mitochondrial motility and neurite outgrowth in apoE4-expressing neuronal cells. These benefits were apoE4-specific and dose-dependent. Modifying CB9032258 yielded well defined structure-activity relationships and more active compounds with enhanced potencies in the FRET assay (IC(50) of 23 and 116 nm, respectively). These compounds efficiently restored functional activities of apoE4-expressing cells in secondary assays. An EPR binding assay showed that the apoE4 structure correction resulted from direct interaction of a phthalazinone. With these data, a six-feature pharmacophore model was constructed for future drug design. Our results serve as a proof of concept that pharmacological intervention with apoE4 structure correctors negates apoE4 detrimental effects in neuronal cells and could be further developed as an Alzheimer disease therapeutic.