Investigating the effect of TRPV4 inhibition on pulmonary-vascular barrier permeability following segmental endotoxin challenge.

Autor: Mole S; GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK. Electronic address: sarah.x.mole@gsk.com., Harry A; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Fowler A; GlaxoSmithKline, Stockley Park, West Uxbridge, Middlesex, UB11 1BT, UK., Hotee S; GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK., Warburton J; GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK., Waite S; GlaxoSmithKline, Stockley Park, West Uxbridge, Middlesex, UB11 1BT, UK., Beerahee M; GlaxoSmithKline, Gunnells Wood Road, Stevenage, UK., Behm DJ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Badorrek P; Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany., Müller M; Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany., Faulenbach C; Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany., Lazaar AL; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Hohlfeld JM; Fraunhofer-Institut Fuer Toxikologie und Experimentelle Medizin [ITEM], Nikolai-Fuchs-Straße 1, 30625, Hannover, Germany; Hannover Medical School and German Centre for Lung Research, Medizinische Hochschule Hannover OE6876, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Jazyk: angličtina
Zdroj: Pulmonary pharmacology & therapeutics [Pulm Pharmacol Ther] 2020 Oct; Vol. 64, pp. 101977. Date of Electronic Publication: 2020 Nov 13.
DOI: 10.1016/j.pupt.2020.101977
Abstrakt: Background: Acute Respiratory Distress Syndrome (ARDS) is associated with increased pulmonary-vascular permeability. In the lung, transient receptor potential vanilloid 4 (TRPV4), a Ca 2+ -permeable cation channel, is a regulator of endothelial permeability and pulmonary edema. We performed a Phase I, placebo-controlled, double-blind, randomized, parallel group, proof-of-mechanism study to investigate the effects of TRPV4 channel blocker, GSK2798745, on pulmonary-vascular barrier permeability using a model of lipopolysaccharide (LPS)-induced lung inflammation.
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.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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