CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin.

The implications of these findings are significant for development of CXCR2 antagonists and other mechanisms targeting neutrophil activation or NETosis, suggesting that IL-8-dependent mechanisms will only work in a subset of COPD patients https://bit.ly/32SeisO.

Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: a randomized, controlled pilot trial.

AIMS: Lung congestion in patients with heart failure (HF) has traditionally been treated using interventions that reduce pulmonary capillary hydrostatic pressure. The transient receptor potential vanilloid 4 (TRPV4) channel regulates fluid transit across the pulmonary capillary-interface, and represents a novel target to reduce lung water, independent of pulmonary capillary hypertension. This pilot study examined the safety and potential efficacy of TRPV4 blockade as a novel treatment for HF. METHODS AND RESULTS: In this randomized, double-blind, placebo-controlled crossover pilot trial, 11 subjects with chronic, compensated HF were treated with a novel TRPV4 antagonist (GSK2798745) or placebo. The primary endpoint was lung diffusing capacity for carbon monoxide (DLCO ) after 7 days of treatment with GSK2798745 as compared to placebo. Secondary endpoints included additional diffusion parameters, spirometry and safety assessments. Compared to placebo, treatment with GSK2798745 resulted in a trend to improvement in DLCO (placebo: -0.336 mL/mmHg/min; GSK2798745: +0.458 mL/mmHg/min; treatment difference: +0.793 mL/mmHg/min; 95% confidence interval: -0.925 to 2.512) that was not statistically significant. GSK2798745 was well-tolerated with no serious adverse events. CONCLUSION: In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF.

Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers.

Daprodustat, a small-molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia-inducible factor (HIF), leading to increased transcription of HIF-responsive genes. This randomized, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14-day repeat-dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Systemic absorption via topical application was limited across doses up to 1.0% at 100 mg/cm2 for 14 days. Systemic pharmacokinetics were quantifiable in a few samples from a few patients. Because only sporadic concentrations were observed versus pharmacokinetic profiles, pharmacokinetic parameters were not determined. Wound area, depth, and volume showed consistent but weak improvements in the treatment arm; however, the variability in response and small sample size of the standard-of-care and placebo arms limited the ability to assess trends in wound healing compared with the daprodustat arm. Overall, topically applied daprodustat was well tolerated, raised no safety concerns, and provided limited to nonquantifiable systemic exposures. The healing of DFUs will need to be evaluated in studies designed to test this hypothesis over a longer treatment duration.

Location, location, location: Assessing the spatial patterning between marijuana licenses, alcohol outlets and neighborhood characteristics within Washington state.

BACKGROUND: The availability of marijuana products is becoming increasingly prevalent across the United States (US), many states are allowing for the production, processing, and retailing of these products for medical and/or recreational use. The purpose of this study is to: (1) examine the spatial patterning of marijuana licenses, and (2) examine the impact of alcohol outlets in addition to other neighborhood characteristics on marijuana licenses within the state of Washington. METHODS: This cross-sectional observational study examined 1458 census tracts in Washington state from 2017, using marijuana and alcohol data from the Washington State Liquor and Cannabis Board as well as neighborhood characteristics data from the American Community Survey 2011-2015 5-year estimates. We used exploratory and formal spatial regression methods, including integrated nested Laplace approximation within a Bayesian statistical framework, to address the study aims. RESULTS: Our results indicate there is significant spatial patterning of marijuana producers and processors across the state. We also found that all marijuana licenses are located in poorer census tracts, and marijuana retailers are co-located in census tracts with off-premises alcohol outlets. CONCLUSIONS: Our study provides empirical evidence of the relationship between marijuana licenses, alcohol outlets, and neighborhood characteristics, and has important implications for policymakers in other states currently considering legalizing marijuana-products for medical and/or recreational use.