The burden of chronic obstructive pulmonary disease associated with maintenance monotherapy in the UK.

BACKGROUND: This study characterized a cohort of chronic obstructive pulmonary disease (COPD) patients on maintenance bronchodilator monotherapy for ≥6 months to establish their disease burden, measured by health care utilization. METHODS: Data were extracted from the UK Clinical Practice Research Datalink and linked to Hospital Episode Statistics. The monotherapy period spanned the first prescription of a long-acting ß2-adrenergic agonist or a long-acting muscarinic antagonist until the end of the study (December 31, 2013) or until step up to dual/triple therapy, for example, addition of another long-acting bronchodilator, an inhaled corticosteroid, or both. A minimum of four consecutive prescriptions and 6 months on continuous monotherapy were required. Patients <50 years old at first COPD diagnosis or with another significant respiratory disease before starting monotherapy were excluded. Disease burden was evaluated by measuring patients' rate of face-to-face interactions with a health care professional (HCP), COPD-related exacerbations, hospitalizations, and referrals. RESULTS: A cohort of 8,811 COPD patients (95% Global initiative for chronic Obstructive Lung Disease stage A/B) on maintenance monotherapy was identified between 2002 and 2013; 45% of these patients were still on monotherapy by the end of the study. Median time from first COPD diagnosis to first monotherapy prescription was 56 days, while the median time on maintenance bronchodilator monotherapy was 2 years. The median number of prescriptions was 14. On average, patients had 15 HCP interactions per year, and one in ten patients experienced a COPD exacerbation (N=8,811). One in 50 patients were hospitalized for COPD per year (n=4,848). CONCLUSION: The average monotherapy-treated patient had a higher than average HCP interaction rate. We also identified a large cohort of patients who were stepped up to triple therapy despite a low rate of exacerbations. The use of the new class of long-acting muscarinic antagonist/long-acting ß2-adrenergic agonist fixed-dose combinations may provide a useful step-up treatment option in such monotherapy patients, before the use of inhaled corticosteroids.

The development of automated patch clamp assays for canonical transient receptor potential channels TRPC3, 6, and 7.

The canonical transient receptor potential channel subfamily (TRPC3, TRPC6, and TRPC7) contains Ca(2+) permeable non-selective cation channels that are widely expressed in a variety of tissues. There is increasing evidence implicating TRPC channels, particularly TRPC3 and 6, in physiological and pathophysiological processes, eliciting interest in these channels as novel drug targets. Electrophysiology remains a benchmark technique for measuring ion channel function and accurately determining the pharmacological effects of compounds. In this report we describe the development of TRPC inhibitor assays on 2 automated planar patch clamp platforms-the IonWorks(®) Quattro™ and QPatch(®) systems. To enable activation of TRPC channels by carbachol, Chinese Hamster Ovary-K1 cells stably expressing the muscarinic M3 receptor were transduced with human TRPC3, TRPC6, or TRPC7 using BacMam viruses. TRPC3, 6, and 7 currents could be recorded on both platforms. However, the design of each platform limits which assay parameters can be recorded. Due to its continuous recording capabilities, the QPatch can capture both the activation and decay of the response. However, the transient nature of TRPC channels, the inability to reactivate and the large variation in peak currents limits the ability to develop assays for compound screening. The IonWorks Quattro, due to its discontinuous sampling, did not fully capture the peak of TRPC currents. However, due to the ability of the IonWorks Quattro to record from 64 cells per well, the variation from well to well was sufficiently reduced allowing for the development of medium-throughput screening assays.

EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa.

Prostaglandin E(2) (PGE(2)) is an inflammatory mediator implicated in several gastrointestinal pathologies that cause diarrhoea. The aim of this study was to establish the contributions of the four different EP receptors (EP(1-4)) to PGE(2)-induced anion secretion in human and mouse colon mucosa. Electrogenic anion secretion (short-circuit current; I(sc)) was measured across colonic mucosae or T84 monolayers placed in Ussing chambers in response to EP receptor agonists and antagonists. PGE(2) and PGE(1)-alcohol increased I(sc) in human colon mucosa, T84 epithelia and mouse colon mucosa, and these responses were inhibited by the EP(4) receptor antagonist, GW627368X alone. In addition, the EP(2) agonist, butaprost increased I(sc) in all three preparations and these responses were inhibited by the non-selective EP(1,2,3) receptor antagonist, AH6809 but not by GW627368X. Conversely, responses mediated by EP(1) and EP(3) receptors were not observed in human colon or T84 monolayers. However, in mouse colon mucosa the EP(3)-preferring agonist, sulprostone reduced I(sc), indicative of G(iα)-signalling. Taken together these results indicate that PGE(2)-induced ion secretion is mediated predominantly by G(s)-coupled EP(4) receptors and also by EP(2) receptors in human mucosa. Furthermore, tumour necrosis factor alpha (TNFα) and interleukin 1beta (IL1ß) increased I(sc) and these responses were also inhibited by the EP(4) receptor antagonist in human colon mucosa. This study establishes the EP receptor pharmacology present in human epithelial preparations, and suggests that EP(4) receptors may be a therapeutic target for the treatment of secretory diarrhoea where PGE(2) is implicated in the aetiology.