Background: Inhaled allergen challenge is a standard method to study airway responses to inflammatory provocation and evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma. MEM 1414 is a novel oral PDE4 inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDE inhibitors. We evaluated the tolerability and effect of MEM 1414 on airway responses in mild asthmatics.

Vasoactive agents may reduce gut mucosal blood flow in the absence of reduced large vessel flow. Constipating drugs do not necessarily reduce gut blood flow. Rectal mucosal blood flow correlates with splenic flexure mucosal flow, and potentially may be used as a more convenient surrogate for studying splenic flexure blood flow.

Nasal allergen challenge (NAC) offers a minimally invasive model with which to study upper airway tissue responses and effects Rationale: of anti-inflammatory therapy.Demonstrate the following: use of synthetic absorptive membranes (SAM) for the collection of nasal lining fluid; use of nasal Objectives: epithelial scrapings for mRNA expression microarray analysis; and dose-dependent effects of single-dose prednisone on NAC responses.A randomized, double-blind, placebo-controlled, 3-period cross-over study was performed in 19 patients with hay fever out of Methods: season. Single-dose oral prednisone (10mg or 25mg) or placebo was administered 1h before challenge with grass pollen extract administered by nasal spray (Bidose, Pfeiffer). The following samples were collected after challenge: SAM (Accuwik Ultra, Pall) eluates for measuring cytokines, nasal lavage cytospins for eosinophil counts, and epithelial curette (Rhinoprobe, Arlington Scientific) samples for gene expression analysis.NAC induced IL-5 and IL-13 in nasal exudates -as measured by geometric mean time weighted averages (GM TWA) of each Results: cytokine concentration (pg/mL) in SAM eluates between 2 and 8 hours after challenge. There was also a robust dose-dependent reduction of this induction as follows. IL-5 fold induction by allergen after pretreatment with: placebo -11.3 (90%CI 4.8 --26.7), 10mg prednisone -3.0 (90% CI 1.3 -7.2), 25mg prednisone -1.4 (90%CI 0.6 -3.3). IL-13: fold induction by allergen after pretreatment with: placebo -7.4 (90%CI 4.0 -13.6), 10mg prednisone -2.8 (90%CI 1.5 -5.2), 25mg prednisone -0.8 (90%CI 0.7 --2.4). Interestingly, IL1β levels were unaffected by allergen, yet were dose-dependently reduced by prednisone. Eosinophils were recovered inconsistently and could not be analyzed. There were no statistically significant differences in total nasal symptom score, although subjects had numerically lower scores on prednisone. Nasal epithelial curettage yielded sufficient high quality RNA for microarray hybridization. These microarray data are being analyzed currently.Oral prednisone causes dose dependent inhibitory effects on levels of IL-5, IL-13, and other cytokines in SAM eluates taken Conclusions: during the late phase following NAC. NAC has the potential to assess pharmacodynamic effects of novel therapeutics in phase I/II studies, to define individual patterns of allergic responses, and define potential responders for specific biologic therapy.