Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.
Background: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. Methods: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatm...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 71; no. 10; pp. 1175 - 1185 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Springer Nature
Oct2015
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=109345385&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 109345385 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Oct2015 vid: 71 iid: 10 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 109345385 109345385 109345385 10.1007/s00228-015-1920-1 109345385 ppf: 1175 ppct: 10 formats: fmt: @attributes: type: P tig: atl: Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects. aug: au: Singh, Dave Siew, Leonard Christensen, Jared Plumb, Jonathan Clarke, Graham Greenaway, Steve Perros-Huguet, Christelle Clarke, Nick Kilty, Iain Tan, Lisa affil: University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Manchester M23 9QZ UK sug: subj: Protein Kinase Inhibitors Administration and Dosage Lipopolysaccharides Administration and Dosage Drug Administration Routes Inflammation Drug Therapy Pulmonary Disease, Chronic Obstructive Drug Therapy Lipopolysaccharides Adverse Effects Human Randomized Controlled Trials Double-Blind Studies Placebos Therapeutic Use Crossover Design Administration, Oral Nebulizers and Vaporizers Fluticasone Administration and Dosage Inflammation Mediators Drug Effects Male Female Adolescence Adult England Immunohistochemistry Protein Kinase Inhibitors Pharmacokinetics Biological Markers Analysis Analysis of Covariance Descriptive Statistics Confidence Intervals Funding Source Adolescent: 13-18 years Adult: 19-44 years Male Female ab: Background: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. Methods: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage. Results: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3 % reduction) by PH-797804 compared to placebo in studies 1 and 2 ( p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0 % reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. Conclusions: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects. pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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