Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).
Whole‐cell recording methods and fluorescence microscopy were used to study the effects of acute exposure to thyroid hormone (T3) on cat atrial myocytes. Acute exposure (≈5 min) to 10 nm T3 significantly increased tetrodotoxin (TTX)‐sensitive inward Na+ current (INa) at voltages between −40 and +20 mV. At maximal INa activation (−40 mV) T3 increased peak INa by 32 %. T3 had no effect on the time course of INa decay, voltage dependence of activation, inactivation, or recovery from inactivation. Comparable exposures to reverse T3 (rT3) or T4 had no effect on INa. L‐type Ca2+ current was unaffected by acute exposure to T3. T3‐induced increases in INa were unaffected by 50 μm nickel, a blocker of T‐type Ca2+ current. T3 significantly increased cell shortening (+62 %) and could elicit spontaneous action potentials arising from Ca2+‐mediated after‐depolarizations. T3 (but not rT3) significantly increased baseline intracellular Ca2+, release of Ca2+ from sarcoplasmic reticulum (SR) and caffeine (10 mm)‐induced release of SR Ca2+. We conclude that acute T3 exposure increases Na+ influx via INa and thereby stimulates reverse‐mode Na+‐Ca2+ exchange to increase intracellular Ca2+ content and release. As a result, T3 increases contraction strength, and can initiate Ca2+‐mediated arrhythmic activity. Acute non‐genomic effects of T3 can contribute to the positive inotropy and sinus (atrial) tachycardia traditionally attributed to chronic, genomic effects of elevated thyroid hormone on atrial muscle.
RATIONALE: Patients with frequent asthma exacerbations resulting in emergency department (ED) visits and hospitalizations are at increased risk for future poor outcomes. Reducing eosinophilic inflammation decreases the frequency and severity of asthma exacerbations and may prove effective in this high-risk population. We examined the ability of a single dose of benralizumab, an investigational anti-interleukin-5 receptor alpha monoclonal antibody, targeting eosinophils in acute severe asthma.METHODS: This was a phase 2, randomized, double-blind, placebo-controlled, parallel-group study of 110 subjects who presented to the ED with an asthma exacerbation, had partial response to standard therapy, and ≥1 additional asthma exacerbation within the previous year. Subjects received either 1 intravenous infusion of placebo (n=38) or benralizumab (0.3 mg/kg, n=36; 1.0 mg/kg, n=36) added to evidence-based outpatient asthma management. Serum samples for the measurement of eosinophil counts were taken at day 0, 7, 42, and 84. Primary outcomes included the proportion of subjects with ≥1 exacerbation and rate of exacerbations at week 12. Secondary outcomes included safety profile, changes in asthma symptoms, health-related quality-of-life measures, lung function, proportion of subjects with ≥1 exacerbation at weeks 4 and 24, and healthcare resource utilization. Subjects were followed with clinic visits to week 12 and with telephone contacts to week 24.RESULTS: Demographic and clinical characteristics of study participants are presented in Table 1. Table 1. Baseline characteristics for the intent-to-treat population Placebo Benralizumab Characteristic (n=38) 0.3 mg/kg (n=36) 1.0 mg/kg (n=36) Total (n=72)Age, mean (range), y
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