ABSTRACT: Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.
25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.
Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.
This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.
Respiratory research 01/2011; 12:140. · 3.36 Impact Factor
ABSTRACT: Extensive evidence in animal models supports a role for IL-13 in the pathobiology of asthma. IMA-638 and IMA-026 are fully humanized IgG(1) antibodies that bind to different epitopes and neutralize IL-13 bioactivity.
We hypothesized that anti-IL-13 treatment would inhibit allergen-induced late-phase asthmatic responses, airway hyperresponsiveness, and inflammation in subjects with asthma.
Fifty-six subjects with mild, atopic asthma were recruited for two double-blind, randomized, placebo-controlled, parallel group trials to compare IMA-638 and IMA-026 IL-13 antibody treatments with placebo treatment. Drug was administered on Days 1 and 8, and allergen challenges were performed on Days 14 and 35. The primary outcome variable was the late-phase area under the curve (AUC), and secondary outcome variables were the early- and late-phase maximum percent fall in FEV(1), early AUC, allergen-induced shift in airway hyperresponsiveness, and sputum eosinophils.
The treatment difference with IMA-638 on Day 14 was -19.1 FEV(1) × hour (95% confidence interval: -36.2, -1.9) for the allergen-induced early AUC and -23.8 FEV(1) × hour (95% confidence interval: -46.4, -1.2) for the late AUC (both P < 0.05), but this effect was lost by Day 35. Treatment with IMA-026 did not attenuate the asthmatic responses on Day 14 or Day 35. There was no effect of either antibody on allergen-induced airway hyperresponsiveness or sputum eosinophils. The frequency of adverse events after administration of the IL-13 antibodies was similar to placebo.
IL-13 has a role in allergen-induced airway responses in humans. Further study is required to determine whether anti-IL-13 monoclonal antibodies will be beneficial clinically.
American Journal of Respiratory and Critical Care Medicine 11/2010; 183(8):1007-14. · 11.08 Impact Factor
ABSTRACT: To determine the magnitude, duration, and consistency of the effects of lung recruitment maneuvers (RMs) on oxygenation, lung mechanics, and comfort in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
We conducted a prospective physiologic study at 3 tertiary-care hospitals. We enrolled 28 consecutive eligible patients with ARDS or ALI and a ratio of P(aO(2)) to fraction of inspired oxygen (P(aO(2))/F(IO(2))) <or= 250 mm Hg while receiving F(IO(2)) >or= 0.50. We performed RMs twice daily for 3 days. The first RM was at 35 cm H(2)O for 20 s. If initial response was equivocal, the clinician immediately administered another RM at a higher pressure (40 cm H(2)O, then 45 cm H(2)O) or for longer period (30 s, then 40 s), in a randomized order. Each patient had up to 6 sets of up to 3 RMs.
Twenty-seven patients met the criteria for ARDS at baseline; 1 had ALI. There was no net effect on oxygenation or pulmonary mechanics following the first or subsequent RMs. The largest rise in P(aO(2)) was from 61 mm Hg to 71 mm Hg, and the largest decrease was 6 mm Hg following the first RM. Augmenting the inflation pressure or duration had no significant effect. These findings precluded analyses about predictors of response or consistency of response. Over the entire study of 122 RMs, 5 patients developed ventilator asynchrony, 3 appeared uncomfortable, 2 experienced transient hypotension, and 4 developed barotrauma that required intervention.
These results do not support the addition of scheduled RMs to usual treatment for ALI or ARDS.
Respiratory care 11/2008; 53(11):1441-9. · 2.01 Impact Factor
Journal of Applied Physiology 06/2006; 100(5):1746. · 3.75 Impact Factor
Journal of Applied Physiology 06/2006; 100(5):1743-7. · 3.75 Impact Factor
ABSTRACT: Efalizumab is a humanized IgG(1) mAb against the lymphocyte function antigen-1 (LFA-1) alpha chain, CD11a. Blocking of LFA-1/intercellular adhesion molecule interactions could inhibit asthmatic inflammation by blocking adhesion and activation of LFA-1-positive leukocytes.
A randomized, double-blinded, placebo-controlled, parallel group, multicenter study investigated the effects of efalizumab on allergen-induced airway responsiveness and airway inflammation.
Thirty-five nonsmoking subjects with mild allergic asthma were randomized to receive efalizumab (n = 24) or placebo (n = 11) in 8 weekly subcutaneous doses (0.7 mg/kg conditioning dose followed by 7 weekly doses of 2.0 mg/kg). Allergen challenges were performed at screening and after 4 and 8 weeks of treatment. Samples of sputum (n = 18 subjects) and blood (n = 35 subjects) were collected the day before challenges, and sputum was collected again at 7 and 24 hours after each challenge. Nonparametric tests were used to compare allergen-induced differences between efalizumab and placebo groups.
Subjects receiving efalizumab developed headache (48%) and flu syndrome (28%) compared to subjects receiving placebo (0%). After 8 weeks of efalizumab, the maximum late percent fall in FEV(1) (late asthmatic response) was inhibited by 50%, but neither the late response nor the late area under the curve was statistically different than placebo (P =.098 and.062, respectively). Efalizumab had no effect on the maximum early percent fall in FEV(1) (early asthmatic response) or early area under the curve compared to placebo (P >.59). Efalizu-mab significantly reduced the postallergen increase in sputum EG2-positive cells and metachromatic cells (P <.05). No other comparisons were statistically different.
Blocking of LFA-1/intercellular adhesion module interactions by efalizumab inhibits the development of allergen-induced cellular inflammatory responses measured in induced sputum and might attenuate the late asthmatic response. Larger studies are needed to confirm this.
Journal of Allergy and Clinical Immunology 09/2003; 112(2):331-8. · 11.00 Impact Factor