Calcilytics for asthma relief

Despite health initiatives for advancing the management of asthma, evidence suggests that many asthmatic subjects have uncontrolled disease. However, the prevalence of uncontrolled asthma in the United States is not known and has not been fully characterized. We sought to assess the prevalence, morbidity, and factors associated with uncontrolled asthma in a nationally representative sample of patients with moderate-to-severe asthma using standard asthma medications. A Web-based survey was administered to patients with diagnoses of asthma for at least 1 year who were receiving multiple controller medications. The Asthma Control Test score was used to stratify respondents into controlled and uncontrolled cohorts. A total of 1812 patients were assessed; 809 (45%) had controlled asthma, and 1003 (55%) had uncontrolled asthma. Most patients had health care coverage and received care from a general practitioner; a large proportion of patients with controlled asthma (74%) and patients with uncontrolled asthma (65%) reported never receiving an asthma action plan. Inhaled corticosteroid plus long-acting beta-agonist was the most common medication regimen in patients with controlled asthma (60%) and patients with uncontrolled asthma (48%) patients. Patients with uncontrolled asthma reported significantly higher rates of health care use. Several comorbidities were predictive of uncontrolled asthma. Uncontrolled asthma is highly prevalent (55%) in patients using standard asthma medications. There is need for improved asthma care in patients with moderate-to-severe asthma, including a global evaluation of asthma control, implementation of treatment plans and asthma control tests, and addressing comorbid conditions. Improved asthma care requires broader assessments of asthma control, including asthma-related health care and medication use, comorbidities, and the implementation of treatment plans and formal asthma control tests.

Severe bronchospasm refractory to β-agonists continues to cause significant morbidity and mortality in asthmatic patients. We questioned whether chloride channels/transporters are novel targets for the relaxation of airway smooth muscle (ASM). We have screened a library of compounds, derivatives of anthranilic and indanyloxyacetic acid, that were originally developed to antagonize chloride channels in the kidney. We hypothesized that members of this library would be novel calcium-activated chloride channel blockers for the airway. The initial screen of this compound library identified 4 of 20 compounds that relaxed a tetraethylammonium chloride-induced contraction in guinea pig tracheal rings. The two most effective compounds, compounds 1 and 13, were further studied for their potential to either prevent the initiation of or relax the maintenance phase of an acetylcholine (ACh)-induced contraction or to potentiate β-agonist-mediated relaxation. Both relaxed an established ACh-induced contraction in human and guinea pig ex vivo ASM. In contrast, the prevention of an ACh-induced contraction required copretreatment with the sodium-potassium-chloride cotransporter blocker bumetanide. The combination of compound 13 and bumetanide also potentiated relaxation by the β-agonist isoproterenol in guinea pig tracheal rings. Compounds 1 and 13 hyperpolarized the plasma cell membrane of human ASM cells and blocked spontaneous transient inward currents, a measure of chloride currents in these cells. These functional and electrophysiological data suggest that modulating ASM chloride flux is a novel therapeutic target in asthma and other bronchoconstrictive diseases.