Difelikefalin for Hemodialysis Patients with Pruritus in Japan.

BACKGROUND: Difelikefalin, a peripherally specific selective agonist of kappa opioid receptors, has been approved for the treatment of pruritus in hemodialysis patients in the United States. However, there is limited evidence for postdialysis intravenous use in non-U.S. populations. METHODS: In this double-blind, placebo-controlled, phase 3 trial in Japan, patients with moderate to severe pruritus were randomly allocated 1:1 to receive either placebo or 0.5 µg/kg of difelikefalin three times per week intravenously for 6 weeks. The primary end point was change from baseline in the Worst Itching Intensity Numerical Rating Scale (NRS; 0 to 10; higher scores indicate more severe itching) score at week 4. RESULTS: A total of 230 patients were screened, of whom 178 were randomly assigned to receive placebo (n=89) or difelikefalin (n=89). The change from baseline in the weekly adjusted mean NRS score (95% confidence interval) at week 4 in the placebo and difelikefalin groups was −1.09 (−1.47 to −0.70) and −2.06 (−2.45 to −1.66), respectively. The difference between the groups was −0.97 (−1.52 to −0.42), demonstrating that difelikefalin was superior to placebo (P<0.001). Prespecified secondary quality-of-life end points showed consistent improvement associated with difelikefalin. The incidence of treatment-related adverse events in the placebo and difelikefalin groups was 3 of 89 patients (3%) and 13 of 89 patients (15%), respectively, of which the majority in the difelikefalin group were gastrointestinal (e.g., constipation and abdominal discomfort). CONCLUSIONS: Intravenous difelikefalin reduced itching and improved quality of life in patients with moderate to severe pruritus who were undergoing maintenance hemodialysis. (Funded by Kissei Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT04711603.)

The ROS-generating oxidase Nox1 is required for epithelial restitution following colitis.

Accumulating evidence suggests that reactive oxygen species (ROS) generated by endogenous metabolic enzymes are involved in a variety of intracellular mechanisms. In particular, superoxide-generating NADPH oxidase (Nox) 1 is highly expressed in the colon and has been implicated in physiological and pathophysiological states of colon tissues. However, its role in tissue repair following colitis has not been fully elucidated. Our study using experimental colitis in mice showed that repair of the mucosal layer did not occur in Nox1-deficient mice following dextran sulfate sodium-induced colitis. This was accompanied by inhibition of proliferation, cell survival, migration, and terminal differentiation (generation of goblet cells) of crypt progenitor cells, as determined by histochemical analyses. Furthermore, Nox1 expression as well as ROS production in the colon crypt was increased during the repair process, and Nox1 deficiency suppressed these events. The results suggest that Nox1 promotes colon mucosal wound repair by sustaining the bioactivity of crypt progenitor cells and plays a crucial role in the epithelial restitution in the case of damage associated with colitis.