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Inhibition of pulmonary inflammation by Roflumilast
S218 Abstracts
J ALLERGY CLIN IMMUNOL FEBRUARY 2004
MONDAY 773
Inhibition of Pulmonary Inflammation by Roflumilast: Effects on the Time Course of Cell Infiltration, Total Protein Accumulation, and Mediator Release in OVA-Challenged Brown Norway Rats
R. Beume, A. Ostermann, J. Barsig, D. Marx, A. Wohlsen, L. Wollin, D. Bundschuh; Pharmacology Inflammation, ALTANA Pharma AG, Konstanz, GERMANY. RATIONALE: Bronchial asthma is characterized by infiltration of immuno-competent cells and release of pro-inflammatory mediators into the airways. These phenomena are seen also in ovalbumin (OVA)-sensitized and OVA-challenged animals. Roflumilast, a novel, potent, selective
J ALLERGY CLIN IMMUNOL VOLUME 113, NUMBER 2
Abstracts S219
MONDAY
PDE4 inhibitor has demonstrated anti-inflammatory activity and is in clinical development for the treatment of COPD and asthma. The effect of Roflumilast on the time course of cell influx, protein accumulation, and pro-inflammatory mediator release in lungs of OVA-challenged Brown Norway (BN) rats was investigated. METHODS: OVA-sensitized BN rats received a single dose of 2mg/kg Roflumilast p.o. or placebo 1h before aerosol OVA-challenge. Bronchoalveolar lavage (BAL) was done at 0.5 and up to 168h after OVA-challenge. At each time point, differential cell counts, concentrations of total protein, and mediators IL-13, eotaxin, and TNFα were determined. RESULTS: Total cells, lymphocytes, neutrophils, and eosinophils were increased in BAL fluids of OVA- vs. non-challenged rats with peak values between 24 and 48h. Maximum protein concentration was reached at 48h. Peak values of IL-13, eotaxin, and TNFα were observed after 48h of OVA-challenge. Roflumilast-treated rats showed significantly delayed and reduced cell infiltration (peak at 72h vs. 48h). The inhibition calculated as AUC was 50% for total cells, 53% for eosinophils, and 38% for neutrophils vs. placebo. Release of IL-13, eotaxin, and TNFα was significantly inhibited by Roflumilast (64%, 65%, and 51%) vs. placebo. CONCLUSIONS: Roflumilast was highly effective in suppressing pulmonary inflammation processes at early stages. Thus, these multi-pathway inhibitory effects suggest that Roflumilast has potent anti-inflammatory properties which contribute to its clinical efficacy. Funding: ALTANA Pharma AG
J ALLERGY CLIN IMMUNOL FEBRUARY 2004
MONDAY 773
Inhibition of Pulmonary Inflammation by Roflumilast: Effects on the Time Course of Cell Infiltration, Total Protein Accumulation, and Mediator Release in OVA-Challenged Brown Norway Rats
R. Beume, A. Ostermann, J. Barsig, D. Marx, A. Wohlsen, L. Wollin, D. Bundschuh; Pharmacology Inflammation, ALTANA Pharma AG, Konstanz, GERMANY. RATIONALE: Bronchial asthma is characterized by infiltration of immuno-competent cells and release of pro-inflammatory mediators into the airways. These phenomena are seen also in ovalbumin (OVA)-sensitized and OVA-challenged animals. Roflumilast, a novel, potent, selective
J ALLERGY CLIN IMMUNOL VOLUME 113, NUMBER 2
Abstracts S219
MONDAY
PDE4 inhibitor has demonstrated anti-inflammatory activity and is in clinical development for the treatment of COPD and asthma. The effect of Roflumilast on the time course of cell influx, protein accumulation, and pro-inflammatory mediator release in lungs of OVA-challenged Brown Norway (BN) rats was investigated. METHODS: OVA-sensitized BN rats received a single dose of 2mg/kg Roflumilast p.o. or placebo 1h before aerosol OVA-challenge. Bronchoalveolar lavage (BAL) was done at 0.5 and up to 168h after OVA-challenge. At each time point, differential cell counts, concentrations of total protein, and mediators IL-13, eotaxin, and TNFα were determined. RESULTS: Total cells, lymphocytes, neutrophils, and eosinophils were increased in BAL fluids of OVA- vs. non-challenged rats with peak values between 24 and 48h. Maximum protein concentration was reached at 48h. Peak values of IL-13, eotaxin, and TNFα were observed after 48h of OVA-challenge. Roflumilast-treated rats showed significantly delayed and reduced cell infiltration (peak at 72h vs. 48h). The inhibition calculated as AUC was 50% for total cells, 53% for eosinophils, and 38% for neutrophils vs. placebo. Release of IL-13, eotaxin, and TNFα was significantly inhibited by Roflumilast (64%, 65%, and 51%) vs. placebo. CONCLUSIONS: Roflumilast was highly effective in suppressing pulmonary inflammation processes at early stages. Thus, these multi-pathway inhibitory effects suggest that Roflumilast has potent anti-inflammatory properties which contribute to its clinical efficacy. Funding: ALTANA Pharma AG