Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis.Eligible subjects were adults with idiopathic pulmonary fibrosis of ,3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo.Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n5119) or placebo (n559). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients.In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. @ERSpublications Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point

We delivered controlled radio frequency energy to the airways of anesthetized, ventilated dogs to examine the effect of this treatment on reducing airway narrowing caused by a known airway constrictor. The airways of 11 dogs were treated with a specially designed bronchial catheter in three of four lung regions. Treatments in each of the three treated lung regions were controlled to a different temperature (55, 65, and 75 degrees C); the untreated lung region served as a control. We measured airway responsiveness to local methacholine chloride (MCh) challenge before and after treatment and examined posttreatment histology to 3 yr. Treatments controlled to 65 degrees C as well as 75 degrees C persistently and significantly reduced airway responsiveness to local MCh challenge (P < or = 0.022). Airway responsiveness (mean percent decrease in airway diameter after MCh challenge) averaged from 6 mo to 3 yr posttreatment was 79 +/- 2.2% in control airways vs. 39 +/- 2.6% (P < or = 0.001) for airways treated at 65 degrees C, and 26 +/- 2.7% (P < or = 0.001) for airways treated at 75 degrees C. Treatment effects were confined to the airway wall and the immediate peribronchial region on histological examination. Airway responsiveness to local MCh challenge was inversely correlated to the extent of altered airway smooth muscle observed in histology (r = -0.54, P < 0.001). We conclude that the temperature-controlled application of radio frequency energy to the airways can reduce airway responsiveness to MCh for at least 3 yr in dogs by reducing airway smooth muscle contractility.

Bronchial thermoplasty is a procedure now being tested in humans for the treatment of asthma. Current studies focusing on safety are encouraging. The procedure, which causes extensive ablation of airway smooth muscle (ASM), is well tolerated, and there is a sustained reduction in airway responsiveness to methacholine. Two assumptions underlie the development of this procedure: 1) ASM is a vestigial tissue; and 2) that treatment directed at ASM alone will provide sustained symptomatic and physiological improvement in asthmatic humans. Even if this procedure is efficacious, it must be safe in the long-term. Current studies in animals and humans suggest that this is very likely to be the case.While bronchial thermoplasty may have a broad application, especially for patients who wish for a permanent amelioration of their symptoms or have difficulty adhering to medical regimens, the compelling use of this procedure is for patients who are inadequately controlled on current drug therapy or who cannot adhere to therapeutic regimens. The application of this procedure for the treatment of asthma is currently being considered by regulatory agencies, and study centres are currently disseminated throughout North America and Europe. Within the next 1–2 yrs, a profile of the potential role of this therapy in human asthma should be developed fully.

In patients with severe asthma, MRI regionally identifies the inflammatory and noninflammatory components of airway disease. Ventilation heterogeneity persists postsalbutamol in patients with uncontrolled eosinophilic bronchitis, which may be the functional consequence of airway inflammation.