Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge.
Acute respiratory distress syndrome (ARDS)
Bronchoalveolar lavage (BAL)
GSK2798745
Segmental lipopolysaccharide (LPS) challenge
Transient receptor potential vanilloid 4 (TRPV4)
Urea-correction
Journal
Pulmonary pharmacology & therapeutics
ISSN: 1522-9629
Titre abrégé: Pulm Pharmacol Ther
Pays: England
ID NLM: 9715279
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
07
08
2020
revised:
20
10
2020
accepted:
10
11
2020
pubmed:
16
11
2020
medline:
18
9
2021
entrez:
15
11
2020
Statut:
ppublish
Résumé
Acute Respiratory Distress Syndrome (ARDS) is associated with increased pulmonary-vascular permeability. In the lung, transient receptor potential vanilloid 4 (TRPV4), a Ca Healthy participants were randomized 1:1 to receive 2 single doses of GSK2798745 or placebo, 12 h apart. Two hours after the first dose, participants underwent bronchoscopy and segmental LPS instillation. Total protein concentration and neutrophil counts were measured in bronchoalveolar lavage (BAL) samples collected before and 24 h after LPS challenge, as markers of barrier permeability and inflammation, respectively. The primary endpoint was baseline adjusted total protein concentration in BAL at 24 h after LPS challenge. A Bayesian framework was used to estimate the posterior probability of any percentage reduction (GSK2798745 relative to placebo). Safety endpoints included the incidence of adverse events (AEs), vital signs, 12-lead electrocardiogram, clinical laboratory and haematological evaluations, and spirometry. Forty-seven participants were dosed and 45 completed the study (22 on GSK2798745 and 23 on placebo). Overall, GSK2798745 was well tolerated. Small reductions in mean baseline adjusted BAL total protein (~9%) and neutrophils (~7%) in the LPS-challenged segment were observed in the GSK2798745 group compared with the placebo group; however, the reductions did not meet pre-specified success criteria of at least a 95% posterior probability that the percentage reduction in the mean 24-h post LPS BAL total protein level (GSK2798745 relative to placebo) exceeded zero. Median plasma concentrations of GSK2798745 were predicted to inhibit TRPV4 on lung vascular endothelial cells by ~70-85% during the 24 h after LPS challenge; median urea-corrected BAL concentrations of GSK2798745 were 3.0- to 8.7-fold higher than those in plasma. GSK2798745 did not affect segmental LPS-induced elevation of BAL total protein or neutrophils, despite blood and lung exposures that were predicted to be efficacious. CLINICALTRIALS. NCT03511105.
Sections du résumé
BACKGROUND
Acute Respiratory Distress Syndrome (ARDS) is associated with increased pulmonary-vascular permeability. In the lung, transient receptor potential vanilloid 4 (TRPV4), a Ca
METHODS
Healthy participants were randomized 1:1 to receive 2 single doses of GSK2798745 or placebo, 12 h apart. Two hours after the first dose, participants underwent bronchoscopy and segmental LPS instillation. Total protein concentration and neutrophil counts were measured in bronchoalveolar lavage (BAL) samples collected before and 24 h after LPS challenge, as markers of barrier permeability and inflammation, respectively. The primary endpoint was baseline adjusted total protein concentration in BAL at 24 h after LPS challenge. A Bayesian framework was used to estimate the posterior probability of any percentage reduction (GSK2798745 relative to placebo). Safety endpoints included the incidence of adverse events (AEs), vital signs, 12-lead electrocardiogram, clinical laboratory and haematological evaluations, and spirometry.
RESULTS
Forty-seven participants were dosed and 45 completed the study (22 on GSK2798745 and 23 on placebo). Overall, GSK2798745 was well tolerated. Small reductions in mean baseline adjusted BAL total protein (~9%) and neutrophils (~7%) in the LPS-challenged segment were observed in the GSK2798745 group compared with the placebo group; however, the reductions did not meet pre-specified success criteria of at least a 95% posterior probability that the percentage reduction in the mean 24-h post LPS BAL total protein level (GSK2798745 relative to placebo) exceeded zero. Median plasma concentrations of GSK2798745 were predicted to inhibit TRPV4 on lung vascular endothelial cells by ~70-85% during the 24 h after LPS challenge; median urea-corrected BAL concentrations of GSK2798745 were 3.0- to 8.7-fold higher than those in plasma.
CONCLUSIONS
GSK2798745 did not affect segmental LPS-induced elevation of BAL total protein or neutrophils, despite blood and lung exposures that were predicted to be efficacious. CLINICALTRIALS.
GOV IDENTIFIER
NCT03511105.
Identifiants
pubmed: 33189900
pii: S1094-5539(20)30182-6
doi: 10.1016/j.pupt.2020.101977
pii:
doi:
Substances chimiques
Benzimidazoles
0
Endotoxins
0
GSK2798745
0
Lipopolysaccharides
0
Spiro Compounds
0
TRPV Cation Channels
0
TRPV4 protein, human
0
Banques de données
ClinicalTrials.gov
['NCT03511105']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
101977Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.