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

Abstract. Background-Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. Aims-To assess the efficacy of topical SCFA treatment in ulcerative colitis. Patients and Methods-103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. Results-Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p=0 14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (<6 months, n=42), more responded to SCFA than to placebo (48% v 18%, p=003). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p=0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p<0.02) in their clinical and histological activity scores. Conclusions-Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit. (Gut 1997; 40: 485-491) Keywords: short chain fatty acids, distal ulcerative colitis.Treatment of distal ulcerative colitis consists mainly of topical or oral 5-aminosalicylic acid (5-ASA) compounds or corticosteroids, or both. These compounds alter the inflammatory response by decreasing oxygen free radical activity and proinflammatory cytokine release, and by modifying the lipo-and cyclooxygenase pathways of arachidonic acid metabolism.' They are relatively expensive, not uniformly effective, are not free of undesired systemic effects even in their new formula-

To determine if organic anions contribute to the diarrhea of inflammatory bowel disease, we measured osmolality, electrolytes, short-chain fatty acids, lactic acid, and some Krebs cycle anions in 24-hr fecal collections from 18 patients with chronic ulcerative colitis, 20 with Crohn's disease of the colon, and 16 normals. Mean lactic acid concentration was significantly elevated in ulcerative and Crohn's colitis, but values correlated with fecal weight only in the former syndrome. In ulcerative colitis, concentrations of each short-chain fatty acid, especially butyrate, were decreased compared with those from normals or Crohn's disease. Lactate and short-chain fatty acids accounted for nearly half the variability in fecal weight in ulcerative colitis. Crohn's patients had elevated mean fecal water osmolality and osmotic gap not observed in ulcerative colitis. Increased lactic acid and/or deficient short-chain fatty acids may modulate the diarrhea of ulcerative colitis. This mechanism seems less important in Crohn's colitis where an additional osmotic component may be significant.

Colon cells from patients with ulcerative colitis utilize short-chain fatty acids inefficiently and may be exposed to decreased concentrations of these compounds. To test whether irrigation of the inflamed mucosa with short-chain fatty acids is useful, we conducted a six-week preliminary trial in 12 patients with distal colitis. Each patient used twice daily rectal irrigations with 100 ml of a solution containing acetate (80 mM), propionate (30 mM), and butyrate (40 mM). Two patients stopped at three weeks, one because of no improvement and the other because of complete resolution of symptoms. Of the 10 who completed the trial, nine were judged to be at least much improved and showed a change in a mean disease activity index score from 7.9 +/- 0.3 (SE) to 1.8 +/- 0.6 (SE) (P less than or equal to 0.002) and in a mucosal histology score from 7.7 +/- 0.7 (SE) to 2.6 +/- 0.7 (SE) (P less than or equal to 0.002). Thus, ulcerative colitis patients appear to benefit from increased contact with or higher than usual levels of these critical energy substrates.