Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma
Stephen K Field Foothills Medical Centre and Tuberculosis Services, Calgary Health Region, Health Science Centre, 3330 Hospital Dr NW, Calgary, Alberta, T2N 4N1, Canada
Background: Roflumilast is a selective phosphodiesterase-4 inhibitor with a broad range of anti-inflammatory actions. Studies in asthma and chronic obstructive pulmonary disease (COPD) have demonstrated that it can improve lung function and reduce inflammation. Objective: To review the clinical data on roflumilast in COPD and asthma. Methods: A PubMed search using the term roflumilast was used to identify articles, and the bibliographies of the identified articles were reviewed to identify other relevant reports. All roflumilast abstracts from the 2006 and 2007 International Meetings of the American College of Chest Physicians, American Thoracic Society and European Respiratory Society were also reviewed. Results/conclusion: The preliminary studies of roflumilast in COPD and asthma have only shown modest clinical benefits and may be associ- ated with gastrointestinal side effects. Further studies are required to clarify the role of roflumilast in the management of COPD and asthma.
Keywords: airway hyperresponsiveness, asthma, COPD, inflammation, PDE-4 inhibitor, remodeling, roflumilast
1. Introduction
The introduction of long acting bronchodilators, both anticholinergics (LAAC) and 2 agonists (LABA), and inhaled corticosteroids (ICS) has advanced the care of patients with COPD and asthma. Despite the availability of effective inhaler therapy, asthma is not well-controlled in most patients [1]. Patients have difficulties with adherence, employing proper inhaler technique, and many are concerned about the potential for ICS side effects [2]. An effective, daily, orally administered, nonsteroidal anti-inflammatory would be an important management option.
Unfortunately, chronic obstructive pulmonary disease (COPD) continues to be responsible for significant morbidity and mortality [3]. In COPD, it has been suggested that inflammation has deleterious systemic effects, including weight loss and muscle weakness, and is associated with increased risks of atherosclerosis, diabetes, osteoporosis and cancer, in addition to lung damage [4,5]. Moreover, the severity of COPD correlates with the severity of inflammation in the lung [6]. ICS do not control inflammation caused by CD8+ T lymphocytes, CD68+ macro- phages or neutrophils, the most prominent inflammatory cells in the airways and lung parenchyma in COPD [7]. Moreover, COPD patients often have difficulties with inhaled medications. In this population, potential risks from ICS include bruising, reduced bone density, fractures, glaucoma and cataracts [8]. A daily, orally administered, and effective nonsteroidal medication would address some of the deficiencies in patient care.Cyclic AMP enhances smooth muscle relaxation and down- regulates inflammatory activity in the lung [9]. Phosphodi- esterases (PDEs) act by reducing intracellular concentrations of the cyclic nucleotides, cAMP and cGMP [10].
1.1 Theophylline
Theophylline is a nonselective PDE inhibitor which has been prescribed for patients with asthma and COPD since the 1930s because of its beneficial bronchodilating effects [11]. It also has other anti-inflammatory effects, mediated through histone deacetylase activation and adenosine receptor antagonism [11,12]. More recently, it has been recognized to also have immunomodulatory and anti- inflammatory effects at lower plasma levels than those required for bronchodilation [13]. Unfortunately, it has a narrow thera- peutic index and is associated with potentially life-threatening cardiovascular and CNS toxicity. Its metabolism is altered by other medications metabolized by the hepatic CYP450 pathways and it interferes with the metabolism of other medications cleared from the circulation by the liver, either diminishing their therapeutic effect or increasing the risk of toxicity. Another notable concern is that theophylline over- doses are difficult to manage. Routine monitoring of blood levels is mandatory and dose adjustments are necessary in elderly patients, smokers, and in those with cardiovascular and/or liver disease. The introduction or discontinuation of other medications frequently requires a theophylline dose adjustment. A significant advantage of the selective PDE-4 inhibitors is the paucity of drug interactions [11].
1.2 Limitations of inhaled corticosteroids
ICS have important anti-inflammatory effects on various immune effector cells, including CD4+ T lymphocytes and eosinophils, which play important roles in the pathogenesis of asthma. Asthma patients with primarily neutrophilic airway inflammation do not respond as well to ICS [14]. Cigarette smoking and viral infections interfere with the therapeutic effect of ICS by increasing neutrophilic inflammation. ICS are not recommended as monotherapy in COPD because of concerns about their effectiveness and potential side effects with chronic use [7,8]. The relative ineffectiveness of ICS in COPD is at least partly explained by the lesser role of eosinophils compared to CD8+ T lymphocytes, CD68+ macrophages, and neutrophils [6]. Leukotriene (LT) receptor antagonists have a complementary anti-inflammatory effect with ICS, but even the combination is inadequate for some asthma patients and their use is not indicated in COPD [7].
2. Pharmacology
Phosphodiesterases hydrolyze the 3-phosphodiester bond in cyclic nucleotides terminating their effects [9]. Cyclic nucleotides mediate the biological responses to a variety of extracellular signaling molecules including hormones, cytokines, neurotransmitters and drugs by activating protein kinases which phosphorylate transcription factors regulating a variety of functions including ion channel conductance, apoptosis, immune responses, smooth muscle relaxation and platelet aggregation [9]. Cyclic AMP also inhibits airway smooth muscle proliferation by limiting both hypertrophy and hyperplasia [9].
Eleven families of PDEs have been identified [15]. The four members of the PDE-4 isoenzyme family are specific for cAMP [16]. In the CNS, inhibition of PDE-4D causes nausea and vomiting. Neurons in the nodose ganglion, with vagal afferent projections to the gut, express PDE-4D [15]. PDE-4B inhibition does not cause nausea and vomiting, but inhibits the production of various cytokines, chemokines, and interleukins that influence the functions of neutrophils, eosinophils, both CD4+ and cytotoxic CD8+ T lymphocytes, B cells, mono- cytes, macrophages, dendritic cells and mast cells (Table 1) [15]. PDE-4 inhibitors also interfere with the production of pro-inflammatory cytokines and IL-6 by epithelial cells, alter endothelial cell function reducing vascular permeability, and inhibit smooth muscle contrac- tion and neuropeptide release by sensory nerves (Table 2) [17]. The therapeutic index of the PDE-4 inhibitors is determined by their relative effects on PDE-4B and -4D, reducing inflammation and causing emesis, respectively. Another factor that may determine side effects is the relative binding of the PDE-4 inhibitors to the high-affinity and low-affinity rolipram binding sites; greater binding to the are not required for co-administration with erythromycin or ketoconazole [26,27].
2.2 Preclinical data
PDE-4 inhibitors suppress antigen-induced broncho- constriction, airway hyper-reactivity, and eosinophil recruitment [15]. Roflumilast inhibits mediator release from a variety of inflammatory cells (Table 1). It also inhibits airway smooth muscle contraction and microvascular permeability. Roflumilast inhibited antigen-induced tonic contraction in guinea-pig trachea and inhibited serotonin and histamine- mediated smooth muscle contraction in both large and small airways in mechanically ventilated rats and guinea-pigs [28]. It inhibited antigen-induced bronchoconstriction and the late inflammatory cell influx in ovalbumin-sensitized guinea-pigs [28]. Roflumilast attenuated the expected increases in TNF- concentration, total protein and inflammatory high-affinity sites correlates with adverse effects which occur more frequently with cilomilast than roflumilast [11].
The ideal PDE-4 inhibitor would minimally affect PDE-4D activity in the CNS and maximally affect PDE-4B activity in the lungs. Phase III clinical trials have been undertaken with the newer PDE-4 inhibitors, cilomilast and roflumilast, in both COPD and asthma [17]. Cilomilast is more selective for PDE-4D and its clinical development has been suspended because of its side effect profile [17]. Compared to the earlier PDE-4 inhibitors, roflumilast has relatively less PDE-4D activity with similar inhibition of the two isozymes [17]. Although better tolerated than cilomilast, it can also cause headache and gastrointestinal side effects [17].
2.1 Pharmacokinetics
Roflumilast has 80% oral bioavailability and its absorption is not affected by food intake or cigarette smoking [17,18]. Neither magnesium hydroxide nor aluminium hydroxide- based antacids interfere with its absorption [19]. There are no interactions with warfarin or erythromycin and dosing does not have to be adjusted for renal impairment. Both roflumilast and its principle metabolite, N-oxide roflumilast, potently inhibit PDE-4B activity [15]. Time-to-peak concentrations are 1½ and 10 h, and elimina- tion half-lifes are 10 h and 20 h, for roflumilast and its N-oxide metabolite, respectively [15]. Dosing does not need to be adjusted in patients with mildly or moderately severe cirrhosis [20]. There are no significant interactions with salbutamol, budesonide or formoterol [21-23]. Roflumilast does not affect the pharmacokinetics of midazolam and is unlikely to alter the clearance of drugs metabolized by CYP3A4 [24]. Fluvoxamine decreases clearance of both roflumilast and its N-oxide metabolite [25]. Dose adjustments cell content of bronchoalveolar lavage specimens in ovalbumin-sensitized brown Norway rats undergoing antigen-challenge [29]. Although neutrophil influx and TNF- production were reduced after allergen-challenge, roflumilast did not reduce serotonin-induced broncho- constriction in brown Norway rats, indicating that its effects were anti-inflammatory rather than bronchodilatory [29]. Pretreatment with roflumilast inhibited bronchoconstriction and decreased intrapulmonary levels of the cysteinyl LTs and LTB4 after ovalbumin-induced bronchoconstriction in sensitized guinea-pigs. However, it did not inhibit LTD4- induced bronchoconstriction, further evidence that its effect is anti-inflammatory rather than bronchodilatory [30].
In Sprague-Dawley rats, roflumilast inhibited leukocyte- endothelial interaction, expression of E-selectin, which mediates the adhesion and recruitment of neutrophils, and microvascular permeability, decreasing inflammatory cell influx and protein extravasation [31]. In summary, roflumilast exhibited anti-inflammatory and anti-allergic properties, and inhibited allergen-induced bronchoconstriction in these animal models.
Roflumilast has greater anti-inflammatory activity in human leukocytes than cilomilast [32,33]. Both roflumilast and roflumilast N-oxide reduced expression of CD11 on human neutrophils and reduced E-selectin expression and the permeability of human umbilical venous endothelial cell monolayers [31]. Lipopolysaccharide-stimulated TNF- pro- duction was reduced in human subjects taking roflumilast 500 µg daily [34].
Airway remodeling, including inflammation, smooth muscle thickening and collagen deposition, is a feature of severe persistent asthma [35]. Growth factors, cytokines and matrix proteins contribute to this process. Corticosteroids prevent inflammation, but do not prevent or reverse remodeling. Since fibroblasts express PDE-4, it is not surprising that roflumilast and its N-oxide metabolite inhibit fibroblast activity [36,37]. Roflumilast, but not LABAs or the corticosteroids, fluticasone or budesonide, decreased fibronectin deposition by airway smooth muscle cells from patients with and without asthma that were stimulated with TGF- [38]. Roflumilast but neither LABAs or corticosteroids decreased production of connective tissue growth factor, collagen 1, and fibronectin from bronchial rings that were stimulated with TGF- [38]. These effects on bronchial rings, smooth muscle and fibroblast activity suggest that roflumilast may inhibit airway remodeling.
3. Clinical data
3.1 Asthma
Roflumilast attenuates the asthmatic response to various stimuli. In a pilot study of 13 subjects with mild allergic asthma, a single 1 mg dose of roflumilast attenuated acute airway hyper-reactivity and improved FEV1 9 h after allergen challenge [39]. In a 4-week double-blinded, randomized, placebo-controlled crossover trial of roflumilast 500 µg/day, exhaled nitric oxide, urinary LTE4 and airway hyper- responsiveness to adenosine were decreased in a cohort of 52 patients, with an FEV1 of at least 60% of predicted [40]. Twenty-five male patients with mild allergic asthma were given roflumilast 500 µg/day, or placebo for 14 days in a double-blinded, randomized, crossover study. Allergen challenge was performed on day 14. Roflumilast inhibited allergen-induced late phase bronchoconstriction and airway hyper-reactivity 24 h post challenge. It also decreased neutrophils, eosinophils, and eosinophilic cationic protein levels in sputum [41]. Sixteen males with exercise-induced asthma were randomized to receive placebo or roflumilast 500 µg daily, for 28 days in a double-blind, crossover trial [34]. They underwent exercise testing on the first, 14th and 28th day of therapy. The reduction in the maximum FEV1 decline during exercise was 14, 24, and 41% (p 0.02), on days 1, 14, and 28, respectively, with roflumilast [34]. Twenty-three subjects with mild asthma participated in a 3-period crossover study, including treatment with placebo, roflumilast, 250 µg/day, and roflumilast 500 µg/day for 7 – 10 days [42]. Each treatment period was separated by minimum washout periods of two weeks. Allergen challenge was performed at the end of each treat- ment period with a single allergen identified by skin prick testing in each subject; one of house dust mite, cat hair, or grass pollen [42]. Both doses of roflumilast reduced the early and late asthmatic reactions, defined as the fall in FEV1 over time, compared to placebo. The differences in the early and late asthmatic reactions during treatment with roflumilast 250 and 500 µg/day were not statistically different [42]. Roflumilast also reduced symptoms of allergic rhinitis [43].
An international study comparing the effects of 3 daily doses of roflumilast given for 12 weeks but without a placebo arm, demonstrated improvements in FEV1, morning and evening peak flow rates, asthma symptom scores and rescue inhaler use [44]. All three doses studied, roflumilast 100, 250 and 500 µg/day, improved lung function. At 12 weeks, the improvements in forced expiratory volume in 1 sec (FEV1) were 260, 320, and 400 ml, respectively. The improvement in FEV1 was evident after 1 week and was maintained at 12 weeks. There were dose-related increases in FEV1 of 260, 320 and 400 ml, at the 100, 250, and 500 µg/day doses, respectively, and the difference between FEV1 in the groups taking roflumilast 100 and 500 µg/day were statistically significant at one and at 12 weeks [44]. Another large international clinical trial compared treatment with daily roflumilast 500 µg to twice daily inhaled beclometasone (BDP) 200 µg for 12 weeks, in patients with moderately severe persistent asthma [45].The FEV1 improved from baseline similarly in both study arms (roflumilast: 270 30 ml, BDP: 320 30 ml; p < 0.0001 in both groups, p nonsignificant between the two groups). The most common adverse event in both groups was asthma worsening. Nausea, headache and diarrhea occurred in 6, 4, and 3% of the roflumilast patients,respectively, compared to 1, 1, and 0% (none) of the BDP patients, respectively [45]. 3.2 Chronic obstructive pulmonary disease In COPD, pathological changes of the small airways and lung parenchyma include inflammatory cell infiltration and fibrous tissue deposition that cause airflow obstruction because of the resulting airway wall thickening and luminal narrowing [46]. Moreover, parenchymal destruction reduces elastic recoil further reducing airflow. Progression of COPD is associated with progressive airway thickening and with an increased number of inflammatory cells, including neutrophils, macrophages, B cells, and CD4+ and CD8+ lymphocytes. The inflammation in COPD is not as respon- sive to corticosteroids as in asthma. Potential advantages of roflumilast over corticosteroids in COPD are that its anti-inflammatory effects extend to most inflammatory cells and that it inhibits the production of various cytokines, matrix proteins and growth factors by airway smooth muscle cells and fibroblasts that may contribute to remodeling [15,38]. In a murine model, roflumilast reduced the number of neutrophils and IL-10 concentration in bronchoalveolar lavage specimens after cigarette smoke exposure [47]. In mice exposed to cigarette smoke for seven months, roflumilast decreased lung macrophage density, prevented a reduction in lung desmosine content and prevented the development of emphysema [47]. Roflumilast did not prevent smoke-associated goblet cell metaplasia. In guinea-pigs exposed to cigarette smoke for 11 days, roflumilast significantly reduced neutrophils, eosinophils, lymphocytes, and protein concentration in bronchoalveolar lavage specimens compared to control smoke-exposed animals [48]. Macrophages were decreased by 68%, but the difference was not statistically significant. In comparison, methylprednisolone significantly decreased eosinophils, but only had a minor effect on other cell lines and protein concentration [48]. A placebo-controlled, crossover study in 38 patients with a mean FEV1 of 61 13% demonstrated that roflumilast 500 µg daily, for 4 weeks did not reduce the percentage of sputum neutrophils in COPD patients, but the absolute numbers of neutrophils and eosinophils, soluble IL-8, neutrophil elastase, eosinophilic cationic protein, and 2 macroglobulin in sputum, and TNF- release from blood cells were reduced [47]. The mean FEV1 was 69 ml higher with roflumilast [49]. A large, double-blinded, randomized, placebo-controlled, parallel-designed international trial, compared 24 weeks treatment with daily roflumilast, both 250 and 500 µg, to placebo [50]. Spirometric parameters including FEV1 improved and exacerbations were reduced in patients receiving either dose of roflumilast. Over the 24-week study period, postbronchodilator FEV1 declined 45 ml in the placebo group (p 0.0041), increased 29 ml in the 250-µg group (p 0.0134), and increased 51 ml in the 500-µg group (p < 0.0001) [50]. The St George respiratory questionnaire (SGRQ) score improved in the roflumilast study arms, but was just short of the accepted clinically significant change of -4. Compared to placebo, the differ- ence was not statistically significant. More patients taking roflumilast, 22% with 500 µg and 17% with 250 µg, withdrew from the study than the 11% of patients who withdrew from the placebo group [50]. In another large international trial, a cohort of COPD patients with a mean FEV1 41% of predicted, treated with roflumilast 500 µg daily for 1 year, experienced a 39 ml increase in FEV1 compared to the placebo arm [51]. There was no difference in SGRQ score or exacerbation rate between the two groups. The exacerbation rate was less and SGRQ was improved in patients with GOLD stage IV COPD who were treated with roflumilast. Most adverse events were rated as mild-to-moderate and resolved with continued treatment. The most common side effects were diarrhea (9%) and nausea (5%), compared to 3 and 1%, respectively, in the placebo group [51]. A cost-effectiveness analysis found that roflumilast increased the overall treatment costs of COPD, but it would reduce other forms of healthcare use [52]. In patients with severe COPD, the reduction in the number of exacerbations would reduce cost. 4. Conclusions Clinical trials in asthma and COPD indicate that roflumilast has a therapeutic effect in both conditions and that its side effect profile is better than earlier PDE-4 inhibitors. Its effects on airway smooth muscle, fibroblasts, epithelial and endothelial cells could potentially prevent remodeling in asthma. Unlike corticosteroids, roflumilast inhibits neutrophils, CD8+ T lymphocytes and macrophages, in addition to eosinophils, which may be an advantage in patients with COPD. 5. Expert opinion Roflumilast has a modest therapeutic effect in both asthma and COPD when given in combination with short acting bronchodilators [44,45,50,51]. There are no published trials to determine whether it is beneficial as an add-on medication, an important consideration for a drug which has a similar therapeutic profile to theophylline [53]. The need for drug level monitoring and the numerous drug interactions with theophylline are obvious advantages for roflumilast, but new drugs are usually more expensive than the drugs they replace. Roflumilast has a greater anti-inflammatory effect, particularly against neutrophils, but the weak bronchodilating effect of theophylline is absent in roflumilast [30]. However, this will not be a concern in patients already taking potent long-acting bronchodilators. Treatment recommendations for asthma are unlikely to change with the demonstration that roflumilast is better than placebo or equivalent to low dose ICS since eosinophilic inflammation, a feature in most asthma patients, is so responsive to corticosteroid therapy. In a minority of patients, often those with more severe asthma, neutrophilic inflammation predominates and ICS are not as effective [54,55]. This is a logical group of patients to consider treating with roflumilast. A study targeting patients with neutrophilic inflammation, or who have corticosteroid- resistant disease, might help to define the population of asthma patients who will benefit most from roflumilast. The anti-inflammatory effects of roflumilast may be more important in COPD. Whereas corticosteroid-responsive eosinophils and CD4+ T lymphocytes are the predominant inflammatory cell in asthma, the proportions of inflam- matory cells are different in COPD with CD8+ T cells, CD68+ macrophages, and during exacerbations, neutrophils predominating [6]. ICS are more effective against eosinophils and CD4+ lymphocytes and are not recommended as monotherapy in COPD [7]. In addition to its effect on eosinophils, roflumilast alters the inflammatory response of neutrophils, macrophages, and CD8+ T cells, and would be expected to be an effective anti-inflammatory agent in COPD. A 6-month study of treatment with roflumilast in COPD subjects indicated that it improved lung function, quality of life and reduced exacerbation frequency compared to placebo [50]. A subsequent large study of daily roflumilast for 12 months only showed a modest improvement in FEV1 and no improvement in quality of life or exacerbation frequency [51]. Further trials comparing it to other medica- tions are needed to help determine where roflumilast should be added to the COPD treatment algorithm. There are no published studies comparing roflumilast to LAAC-, LABA-, or combination ICS/LABA- therapy in COPD. The modest results of the Rabe et al. and Calverley et al. studies suggest that roflumilast is unlikely to perform well in comparative studies with the long acting bronchodilators [50,51]. This does not preclude a potential role for roflumilast in the management of COPD patients. Although ICS given as monotherapy are not particularly effective in COPD, recently completed studies of treatment with ICS/LABA combination inhalers have demonstrated important beneficial effects in COPD, reducing exacerba- tion frequency, hospitalizations, improving pulmonary function and quality of life, and possibly even reducing mortality [56-59]. Roflumilast has anti-inflammatory effects that are better aligned to combat the pathology of COPD than ICS, and could potentially improve outcomes in combination with long-acting bronchodilators, both LAAC and LABA, not evident when given alone [57,58]. Another potential advantage of treatment with roflumilast instead of ICS is that the use of ICS increases the risk of lower respiratory tract infection in COPD [60]. Future trials of the role of roflumilast in COPD should target conditions, and be compared to ICS, where they have been beneficial [55,56]. To date, there are no published studies looking at a potential role of adding roflumilast to existing treatments, although a placebo-controlled study of the addition of roflumilast to treatment with tiotropium in COPD patients is currently underway [61]. Adequately powered trials comparing treatment with ICS to treatment with roflumilast, in patients with at least moderately severe COPD already being treated with either or both LAAC and LABA, should be undertaken. These studies will be necessary to clarify the role of roflumilast in the management of COPD. Declaration of interest S Field has done clinical trials and/or received honoraria for speaking for the following companies; AstraZeneca, Aventis, Bayer, Nycomed, GSK, Boehringer Ingelheim, Abbott and Ortho-Janssen. Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Fitzgerald JM, Boulet LP, McIvor RA, et al. Asthma control in Canada remains suboptimal: the reality of asthma control (TRAC study). Can Respir J 2006;13:253-9 2. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients. Chest 1998;113:587-92 3. Jemal A, Ward E, Hao Y, et al. Trends in the leading causes of death in the United States, 1970 – 2002. JAMA 2005;294:1255-9 • Discusses mortality due to COPD in USA. 8. Tattersfield AE, Harrison TW, Hubbard RB, et al. Safety of inhaled corticosteroids. Proc Am Thorac Soc 2004;1:171-5 9. Torphy TJ. Phosphodiesterase isozymes. Molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998;157:351-70 •• Comprehensive review of the phosphodiesterase isozyme families. 10. Reid P. Roflumilast Altana Pharma. Current Opin Invest Drugs 2002;3:1165-70 11. Boswell-Smith V, Cazola M, Page CP. Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol 2006;117:1237-43 17. Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005;365:167-75 •• Review of clinical data in COPD and asthma. 18. Hauns B, Hermann R, Huennemeyer A, et al. Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects. J Clin Pharmacol 2006;46:1146-53 19. Nassr N, Lahu G, von Richter O, et al. Magnesium hydroxide/aluminium hydroxide-containing antacid does not affect the pharmacokinetics of the targeted phosphodiesterase 4 inhibitor roflumilast. J Clin Pharmacol 2007;47:660-6 alter the pharmacokinetics of either drug. Am J Respir Crit Care Med 2007;175:A113 24. Nassr N, Lahu G, von Richter O, et al. Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects. Br J Clin Pharmacol 2007;63:365-70 25. von Richter O, Lahu G, Huennemeyer A, et al. Effect of fluvoxamine on the pharmacokinetics of roflumilast and roflumilast N-oxide. Clin Pharmacokinet 2007;46:613-22 26. Lahu G, Huennemeyer A, Herzog R, et al. Effect of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide. Am J Respir Crit Care Med 2006;173:A850 27. Lahu G, Huennemeyer A, Reutter F, et al. Pharmacokinetics of roflumilast and roflumilast N-oxide with concomitant ketoconazole. Am J Respir Crit Care Med 2006;173:A850 28. Bundschuh DS, Eltze M, Barsig J, et al. In vivo efficacy in airway disease models of roflumilast, novel orally active PDE4 inhibitor. J Pharmacol Exp Ther 2001;297:280-90 •• Discusses PDE-4 inhibitor actions in animal models of airway disease. 29. Wollin L, Bundschuh DS, Wohlsen A, et al. Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. Pulm Pharm Ther 2006;19:343-52 • Discusses PDE-4 inhibitor actions in animal models of airway disease. 30. Wollin L, Marx D, Wohlsen A, et al. Roflumilast inhibition of pulmonary leukotriene production and bronchoconstriction in ovalbumin-sensitized and -challenged Guinea pigs. J Asthma 2005;42:873-8 • Discusses PDE-4 inhibitor actions in animal models of airway disease. 31. Sanz M-J, Cortijo J, Taha MA, et al. Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol 2007;152:481-92 • Discusses in vitro actions of roflumilast. 32. Jones NA, Boswell-Smith V, Lever R, Page CP. The effect of selective phosphodiesterase isozyme inhibition on neutrophil function in vitro. 33. Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001;297:267-79 34. Timmer W, Leclerc V, Birraux G, et al. The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo. J Clin Pharmacol 2002;42:297-303 35. Sumi Y, Hamid Q. Airway remodeling in asthma. Allergol Int 2007;56:341-8 • Review of airway remodeling in asthma. 36. Boero S, Silvestri M, Sabatini F, et al. Inhibition of lung fibroblast proinflammatory functions by roflumilast N-oxide. Am J Respir Crit Care Med 2006;173:A33 37. Klar J, Sabatini F, Schatton E, et al. Roflumilast N-oxide reduces human fibroblast function. Eur Respir J 2007;30(Suppl 51):544S 38. Burgess JK, Oliver BG, Poniris MH, et al. A phosphodiesterase 4 inhibitor inhibits matrix protein deposition in airways in vitro. J Allergy Clin Immunol 2006;118:649-57 39. Louw C, Williams Z, Venter L, et al. Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge. Respiration 2007;74:411-7 • Roflumilast inhibits allergen-induced airway hyperresponsiveness. 40. Kanniess F, Beler J, Beeh K-M, et al. Effects of roflumilast on exhaled NO, airway hyperresponsiveness, and inflammatory markers in patients with asthma. Eur Respir J 2006;28(Suppl 50):670S 41. Gauvreau GM, Boulet LP, Cote J, et al. Effects of roflumilast on airway inflammation and function following allergen challenge in patients with allergic asthma. Am J Respir Crit Care Med 2007;175:A484 42. van Schalkwyk E, Strydom K, Williams Z, et al. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions. J Allergy Clin Immunol 2005;116:292-8 43. Schmidt BMW, Kusma M, Feuring M, et al. The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis. J Allergy Clin Immunol 2001;108:530-6 • Roflumilast is effective for allergic rhinitis. 44. Bateman ED, Izqueirdo JL, Harnest U, et al. Efficacy and safety of roflumilast in the treatment of persistent asthma. Ann Allergy Asthma Immunol 2006;96:679-86 • 12-week roflumilast dose-finding study. 45. Bousquet J, Aubier M, Sastre J, et al. Comparison of roflumilast, an oral, anti-inflammatory, with beclomethasone diproprionate in the treatment of persistent asthma. Allergy 2006;61:72-8 • Comparative trial with low-dose beclometasone diproprionate. 46. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 2004;364:709-21 •• Excellent review of COPD pathology. 47. Martorana PA, Beume R, Lucattelli M, et al. Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke. Am J Respir Crit Care Med 2005;172:848-53 • Roflumilast prevented emphysema in smoke-exposed mice. 48. Fitzgerald MF, Spicer D, McAulay AE, et al. Roflumilast but not methylprednisolone inhibited cigarette smoke-induced pulmonary inflammation in guinea pigs. Eur Respir J 2006;28(Suppl 50):663S 49. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:1081-7 50. Rabe K, Bateman ED, O’Donnell D, et al. Roflumilast–an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366:563-71 •• Large 24-week trial of roflumilast in COPD. 51. Calverley PMA, McIvor A, et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:154-61 •• Large 1-year trial of roflumilast in severe COPD. 52. Rutten-van Molken MP, van Nooten FE, Lindemann M, et al. A 1-year prospective cost-effectiveness analysis of roflumilast for the treatment of patients with severe chronic obstructive pulmonary disease. Pharmacoeconomics 2007;25:695-711. 53. Lipworth B. Phosphodiesterase type 4 inhibitors for asthma: a real breakthrough or just expensive theophylline? Ann Allergy Asthma Immunol 2006;96:640-1 54. Green RH, Brightling CE, Woltmann G, et al. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875-9 55. Shannon J, Ernst P, Yamauchi Y, et al. Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 2008;133:420-6 56. Suissa S, McGhan R, Niewohner D, Make B. Inhaled corticosteroids in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2007;4:535-42 57. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. New Engl J Med 2007;356:775-89 •• Large 3-year trial demonstrated that combination of salmeterol/fluticasone was beneficial for COPD patients. 58. Aaron SD, Vandemheen KL,Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med 2007;146:545-55 •• 1-year trial demonstrated that the addition of salmeterol/fluticasone to tiotropium was beneficial but did not reduce the exacerbation rate in COPD. 59. Wedzicha JA, Calverley PMA, Seemungal TA, et al. The prevention of COPD exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177:19-26 60. Ernst P, Gonzalez AV, Brassard P, Suissa S. Inhaled corticosteroid use in obstructive pulmonary disease and the risk of hospitalization for pneumonia. Am J Respir Crit Care Med 2007;176:162-6 • Inhaled corticosteroids increase the risk of pneumonia in COPD. 61. The Helios study BY217/M2-128. 24 weeks treatment with Enpp-1-IN-1 roflumilast or placebo in COPD patients treated with tiotropium 18 µg daily.