Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions

Schalkwyk, Emmerentia van; Strydom, K.; Williams, Zelda; Venter, Louis; Leichtl, S.; Schmid-Wirlitsch, C; Bredenbröker, Dirk; Bardin, Philip G.

doi:10.1016/j.jaci.2005.04.023

Cited by 102 publications

(76 citation statements)

References 22 publications

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“…Furthermore, the LAR AUC for OC000459 in sequence B was greater than placebo in sequence A, suggesting again no effect of OC000459 on the LAR in sequence B. Any possible carry-over effect was also minimised by the use of a 3-week washout period, which is longer than has been used in other allergen challenge studies [12][13][14]. Additionally, there are no pharmacokinetic reasons to explain a duration of action of OC000459 after 3 weeks, as the terminal half-life is 13 h (personal communication) and there are no pharmacologically active metabolites of this drug.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

et al. 2012

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CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a Gprotein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D 2 -driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid-naïve asthmatic patients.A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days' treatment with OC000459 (200 mg twice daily) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study.There was a 25.4% (95% CI 5.1-45.6%) reduction in the LAR area under the curve (AUC) for change in forced expiratory volume in 1 s with OC000459 compared with placebo (p50.018) but no effect on the EAR. Sputum eosinophil counts at 1 day post-allergen challenge were lower after OC000459 treatment (p50.002). PGD 2 -induced blood eosinophil shape change ex vivo was assessed at day 7 (n57). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8--0.4%; p50.048).OC000459 treatment inhibited LAR and post-allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

et al. 2012

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“…reported to be effective in asthmatics [28] and are now in latestage clinical trials for inflammatory pulmonary diseases, although they are limited by their possible side-effect profile.…”

Section: Discussionmentioning

confidence: 99%

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Chevalier¹,

Lagente²,

Dupont³

et al. 2011

Eur Respir J

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Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma.Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice.Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges.For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.

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“…2007; van Schalkwyk et al. 2005). In stable disease, roflumilast and cilomilast have shown significant improvements in lung function and symptom score and may reduce rescue medication use (Bousquet et al.…”

Section: Introductionmentioning

confidence: 99%

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

Edwards

Facchinetti

Civelli

et al. 2016

Pharmacology Res & Perspec

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Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS‐2B), we investigated the potential anti‐inflammatory effects of CHF6001 on rhinovirus (RV1B)‐induced cytokines. Cytokine mRNA was measured by real‐time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7‐point dose–response curve (1000–0.001 nmol/L) as a 1.5‐h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B‐induced IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein in a concentration‐dependent manner. Generally, CHF6001 was 13‐ to 16‐fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL‐8, IL‐29, IP‐10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV‐induced cytokines when compared with steroid or CHF6001 alone. Combined low‐dose steroid and low‐dose CHF6001 had a similar efficacy as high‐dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti‐inflammatory activity against virus‐induced inflammatory mediators and that CHF6001 is more potent than roflumilast.

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Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions

Cited by 102 publications

References 22 publications

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

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