GSK256066 / GSK - LARVOL DELTA

Anti-oxidative and anti-inflammatory effects of the phosphodiesterase 3/4 inhibitor ensifentrine. (PubMed, Int Immunopharmacol) - "Peripheral blood mononuclear cells (PBMCs) from COPD patients and healthy controls and human bronchial epithelial cells were treated with ensifentrine or a PDE4 inhibitor (roflumilast or GSK256066) or dexamethasone prior to exposure to lipopolysaccharide or T-cell receptor activation, with measurement of supernatant levels of TNFα and IFNγ, respectively. We report a novel mechanism of action for ensifentrine, reducing effects of oxidative stress through a PDE3 dependent mechanism. The anti-inflammatory effects of ensifentrine were lower compared to the PDE4 inhibitors tested."

IO biomarker • Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CASP3 • CASP7 • IFNG • TNFA

Anti-inflammatory effects of PDE3/4 inhibitor ensifentrine in peripheral blood mononuclear cells from COPD patients (ERS 2024) - "Peripheral blood mononuclear cells (PBMCs) from COPD patients (N=8) and HNS (N=8) were treated with ensifentrine, the corticosteroid dexamethasone or PDE4 inhibitors roflumilast and GSK256066 (all compounds 0.00001-1µM) for 1h prior to 24h stimulation with LPS (1ug/ml). The maximal effects were similar to corticosteroids and other PDE4 inhibitors, while there were potency differences (IC50) between compounds. These findings support potential anti-inflammatory effects of ensifentrine in COPD."

Clinical • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • TNFA

Acute Lung Functional and Airway Remodeling Effects of an Inhaled Highly Selective Phosphodiesterase 4 Inhibitor in Ventilated Preterm Lambs Exposed to Chorioamnionitis. (PubMed, Pharmaceuticals (Basel)) - "However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental effects and promote lung inflammation in the premature lung...Ventilation-induced structural and functional changes were only modestly ameliorated by a low dose of PDE4 inhibitor. In conclusion, our findings indicate the narrow therapeutic window of PDE4 inhibitors in the developing lung."

Journal • Acute Respiratory Distress Syndrome • Bronchopulmonary Dysplasia • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent. (PubMed, J Aerosol Med Pulm Drug Deliv) - "We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation...Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population."

Journal • Bronchopulmonary Dysplasia • Idiopathic Pulmonary Fibrosis • Immunology • Retinopathy of Prematurity • Vasculitis

Phosphodiesterase 4 inhibitors attenuate virus-induced activation of eosinophils from asthmatics without affecting virus binding. (PubMed, Pharmacol Res Perspect) - "Prior to exposure to virus, eosinophils were treated with vehicle or selective PDE4 inhibitors CHF6001 and GSK256066. Our data indicate that PDE4 inhibitors can attenuate eosinophil activation, without affecting virus binding. By attenuating virus-induced responses, PDE4 inhibitors may mitigate virus-induced asthma exacerbations."

Journal • Asthma • Immunology • Infectious Disease • Respiratory Diseases • CD63

Impact of Phosphodiesterase 4 Inhibition on the Operational Efficacy, Response Maxima and Kinetics of Indacaterol-induced Gene Expression Changes in BEAS-2B Airway Epithelial Cells: A Global Transcriptomic Analysis. (PubMed, Mol Pharmacol) - "Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD. SIGNIFICANCE STATEMENT: The ability of the PDE4 inhibitor, roflumilast, to potentiate gene expression changes in human airway epithelial cells by the long-acting Beta2-adrenoceptor agonist, indacaterol, may contribute to its clinical efficacy in COPD."

Clinical • Journal