Limits...
Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

Singh D, Siew L, Christensen J, Plumb J, Clarke GW, Greenaway S, Perros-Huguet C, Clarke N, Kilty I, Tan L - Eur. J. Clin. Pharmacol. (2015)

Bottom Line: We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response.PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects.Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

View Article: PubMed Central - PubMed

Affiliation: University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Manchester, M23 9QZ, UK. dsingh@meu.org.uk.

ABSTRACT

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.

No MeSH data available.


Inhibition of LPS induced sputum neutrophil percentage. The reduction in sputum neutrophil percentage caused by active treatments compared to placebo are shown; bars are mean difference and error bars are 90 % CI (*p < 0.05 and **p < 0.01 from ANCOVA model)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4564450&req=5

Fig2: Inhibition of LPS induced sputum neutrophil percentage. The reduction in sputum neutrophil percentage caused by active treatments compared to placebo are shown; bars are mean difference and error bars are 90 % CI (*p < 0.05 and **p < 0.01 from ANCOVA model)

Mentions: There was a statistically significant inhibition of the sputum neutrophil percentage post-LPS challenge caused by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), with 15.1 and 15.3 % reduction in mean sputum neutrophil percentage (Fig. 2), representing approximately 50 % attenuation of the modelled LPS response. Study 2 also showed significant inhibition of sputum neutrophil percentage post LPS challenge after administration of PF-03715455 of 8.0 % which was approximately 25 % attenuation of the modelled LPS response (p = 0.031). Sputum neutrophil percentage post-LPS challenge was not changed significantly by fluticasone propionate (p = 0.55).Fig. 2


Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

Singh D, Siew L, Christensen J, Plumb J, Clarke GW, Greenaway S, Perros-Huguet C, Clarke N, Kilty I, Tan L - Eur. J. Clin. Pharmacol. (2015)

Inhibition of LPS induced sputum neutrophil percentage. The reduction in sputum neutrophil percentage caused by active treatments compared to placebo are shown; bars are mean difference and error bars are 90 % CI (*p < 0.05 and **p < 0.01 from ANCOVA model)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4564450&req=5

Fig2: Inhibition of LPS induced sputum neutrophil percentage. The reduction in sputum neutrophil percentage caused by active treatments compared to placebo are shown; bars are mean difference and error bars are 90 % CI (*p < 0.05 and **p < 0.01 from ANCOVA model)
Mentions: There was a statistically significant inhibition of the sputum neutrophil percentage post-LPS challenge caused by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), with 15.1 and 15.3 % reduction in mean sputum neutrophil percentage (Fig. 2), representing approximately 50 % attenuation of the modelled LPS response. Study 2 also showed significant inhibition of sputum neutrophil percentage post LPS challenge after administration of PF-03715455 of 8.0 % which was approximately 25 % attenuation of the modelled LPS response (p = 0.031). Sputum neutrophil percentage post-LPS challenge was not changed significantly by fluticasone propionate (p = 0.55).Fig. 2

Bottom Line: We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response.PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects.Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

View Article: PubMed Central - PubMed

Affiliation: University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Manchester, M23 9QZ, UK. dsingh@meu.org.uk.

ABSTRACT

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.

No MeSH data available.