Roflumilast for asthma: Safety findings from a pooled analysis of ten clinical studies.

BACKGROUND: The safety profile of roflumilast, a phosphodiesterase 4 inhibitor, has been extensively researched in patients with chronic obstructive pulmonary disease (COPD). Adverse events (AEs) including headache, diarrhoea and weight loss have been reported. Much less is known about the safety of roflumilast treatment in patients with bronchial asthma. AIM: To evaluate the safety and tolerability of roflumilast using safety data from one open-label and ten pooled placebo-controlled phase II and III clinical studies completed between 1997 and 2005. SUBJECTS AND METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 40 weeks. Data for 5169 patients between 12 and 70 years of age, of whom 2851 received roflumilast at doses of 125, 250 and 500 µg, were analyzed. At randomization patients had a forced expiratory flow of 45-100%. RESULTS: Headache was the most frequent AE with an incidence rate of 50 and 29.2 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. Gastrointestinal AEs were common. Nausea and diarrhoea occurred in 28.7 and 28.3 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. The extent of weight loss in roflumilast-treated patients was small. AEs reported in 465 patients in the 4-week open-label follow-up study reflected those of the pooled studies. CONCLUSIONS: The severity and incidence of AEs reported from this pooled safety analysis confirm that roflumilast is generally well tolerated by patients with asthma. This reflects the general safety profile reported previously in patients with COPD. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.

Roflumilast for asthma: Efficacy findings in placebo-controlled studies.

BACKGROUND: The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. AIM: To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo-controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks. Data were analyzed from 4873 patients, 12-70 years of age, of whom 2668 received roflumilast. At randomization patients had a forced expiratory flow (FEV1) of 45-90%. Roflumilast was investigated at doses of 125, 250 and 500 µg versus placebo. In two studies, 500 µg roflumilast was added on top of standard therapy with inhaled corticosteroids (ICS), 250 µg fluticasone propionate, or 400 µg beclomethasone dipropionate (BDP). Improvement in FEV1 from baseline was the primary endpoint in seven studies. Key secondary endpoints included asthma symptom scores and time to first severe exacerbation. RESULTS: Roflumilast consistently improved FEV1 across the nine studies compared with placebo, reaching statistical significance in three studies. When given in addition to ICS, roflumilast provided additional improvements in FEV1 which was statistically significant for 500 µg roflumilast/400 µg BDP versus placebo/400 µg BDP. CONCLUSION: Together these studies show that roflumilast has potential as an effective anti-inflammatory therapy for the treatment of asthma. Additional beneficial effects are observed when given in combination with ICS, which warrant further investigation. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.

Roflumilast for asthma: Efficacy findings in non-placebo-controlled comparator and dosing studies.

BACKGROUND: Roflumilast, a phosphodiesterase-4 inhibitor, has an established place in the treatment of chronic obstructive pulmonary disease. Its potential role as a treatment for asthma is unclear. AIM: We report the results from seven double-blind, parallel group, phase II or III studies designed to compare roflumilast with two anti-inflammatory treatments, beclomethasone dipropionate (BDP) and montelukast, in patients with asthma. METHODS: The studies of 6-12 week duration were conducted at 309 sites in Europe, North America, South Africa and Australia from 1998 to 2005. Data from 3802 patients, aged 12-70 years who received either roflumilast 100 µg, 250 µg or 500 µg once daily, BDP 400 µg or 500 µg twice daily, or 10 mg montelukast once daily was analyzed. Primary endpoints were mean change and time averaged excess area under the curve in forced expiratory volume in one second (FEV1) over the duration of the study. Secondary endpoints included change in forced vital capacity and peak expiratory flow, asthma symptoms and the concomitant use of rescue medication. RESULTS: Roflumilast was non-inferior to BDP and montelukast and consistently increased FEV1. Use of rescue medication and all asthma symptom scores decreased significantly with all treatments, but no statistically significant between-group differences were observed. Secondary lung function endpoints generally supported the conclusions of the primary outcome measure. CONCLUSIONS: Roflumilast improves FEV1 and asthma symptoms in patients with mild to moderate asthma, and is non-inferior compared with both BDP and montelukast. It deserves further study as a potentially effective anti-inflammatory treatment for asthma.

Roflumilast for asthma: Efficacy findings in mechanism of action studies.

BACKGROUND: The efficacy profile of roflumilast, a phosphodiesterase-4 inhibitor used for the treatment of chronic obstructive pulmonary disease (COPD), is well known. In asthma treatment, much less is understood about the role of roflumilast, particularly its mechanism of action and potential bronchodilatory effects. AIM: To evaluate the therapeutic efficacy and mechanism of action of roflumilast in patients with asthma using data from eight placebo-controlled, double-blind phase I-III studies. METHODS: The studies were conducted at 14 sites in Europe, North America and South Africa from 1997 to 2005. The effect of treatment with 250 µg, 500 µg or 1000 µg roflumilast was compared with placebo in seven cross-over studies and one parallel-group study in 197 patients 18-70 years of age. Primary endpoints focused on the extent of the late allergic response after an allergen challenge, change in sputum cell eosinophil counts or exhaled nitric oxide (eNO), forced expiratory volume in 1 s (FEV1) and exercise-induced bronchoconstriction. Secondary endpoints included the extent of the early allergic response and measurements of tumour necrosis factor α (TNFα), sputum cells and inflammatory markers. RESULTS: Roflumilast attenuated allergen-induced bronchoconstriction (FEV1) in patients with asthma. Significant reductions in allergen-induced airway inflammation, including a reduction in both eosinophil and neutrophil counts were also observed and physiologic responses to allergen-induced challenge were confirmed by a significant reduction in TNFα. Side effects were similar to COPD, but did not include weight loss. CONCLUSIONS: The results from these studies indicate that the anti-inflammatory effects of roflumilast observed in COPD are also seen in asthma and advance our understanding of its mechanism of action. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT01365533.

Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus.

CONTEXT: The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism. OBJECTIVE: Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight. DESIGN AND SETTING: We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients. PATIENTS: Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study. INTERVENTIONS: Roflumilast 500 µg or placebo was administered once daily. PRIMARY OUTCOME: We evaluated mean change in blood glycated hemoglobin levels. SECONDARY OUTCOMES: We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters. RESULTS: Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = -0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [-0.7 (0.4) kg] was not statistically significant (P = 0.0584). CONCLUSION: Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis.

Roflumilast with long-acting ß2-agonists for COPD: influence of exacerbation history.

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting ß(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 µg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge.

BACKGROUND: Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, is currently in clinical development for the treatment of asthma. OBJECTIVES: This pilot study examined the effect of roflumilast on allergen-induced airway hyperresponsiveness (AHR) to histamine challenge and asthmatic response to allergen challenge. METHODS: In a randomized, double-blind, 2-period, crossover trial, 13 patients with mild allergic asthma [mean forced expiratory volume in 1 s (FEV(1)) % predicted = 86%] received a single dose of oral roflumilast 1,000 microg or placebo. Patients were administered roflumilast 60 min before allergen challenge, and asthmatic responses were assessed via change in FEV(1)

Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma.

BACKGROUND: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor with anti-inflammatory activity in development for the treatment of asthma. Roflumilast was compared with inhaled beclomethasone dipropionate (BDP) in patients with asthma. METHODS: In a double blind, double-dummy, randomized, noninferiority study, 499 patients (forced expiratory volume in 1 s [FEV1] = 50-85% predicted) received roflumilast 500 microg once daily or BDP 200 microg twice daily (400 microg/day) for 12 weeks. Lung function and adverse events were monitored. RESULTS: Roflumilast and BDP significantly improved FEV1 by 12% (270 +/- 30 ml) and 14% (320 +/- 30 ml), respectively (P < 0.0001 vs baseline). Roflumilast and BDP also significantly improved forced vital capacity (FVC) (P < 0.0001 vs baseline). There were no significant differences between roflumilast and BDP with regard to improvement in FEV1 and FVC. Roflumilast and BDP showed small improvements in median asthma symptom scores (-0.82 and -1.00, respectively) and reduced rescue medication use (-1.00 and -1.15 median puffs/day, respectively; P < 0.0001 vs baseline). These small differences between roflumilast and BDP were not considered clinically relevant. Both agents were well tolerated. CONCLUSIONS: Once daily, oral roflumilast 500 microg was comparable with inhaled twice-daily BDP (400 microg/day) in improving pulmonary function and asthma symptoms, and reducing rescue medication use in patients with asthma.

Effects of the nitric oxide/cGMP system compared with the cAMP system on airway mucus secretion in the rat.

Mucus secretion of the airways is under the control of a variety of intracellular second messenger systems. Cyclic nucleotides such as cGMP, coupled to the recently discovered nitric oxide system, and cAMP are of outstanding interest in this respect. The present study used the modified Ussing chamber technique and mucins labelled with (35)SO(4) to investigate mucus secretion in the rat trachea to clarify the contribution of these different second messenger systems to the control of mucin secretion.A variety of drugs affecting either the generation or the breakdown of the respective cyclic nucleotides were used. Neither drugs interfering with nitric oxide synthase nor the phosphodiesterase isoenzyme responsible for cGMP breakdown nor cGMP analogues were able to affect mucus secretion. In contrast, stimulation of adenylate cyclase or inhibition of the respective phosphodiesterase resulted in a potent increase of mucus secretion. In conclusion, we failed to show the involvement of the nitric oxide/cGMP system, whereas the cAMP system seems to be a very efficient regulator of mucus secretion in the rat trachea.

Effects of selective tachykinin-receptor antagonists on tachykinin-induced airway mucus secretion in the rat.

Tachykinins like substance P (SP), neurokinin A (NKA), neurokinin B (NKB) differentially stimulate airway mucus secretion with the following rank order of potency in rat trachea: SP>NKA>NKB. These differential actions are most likely due to different affinities to the tachykinin receptors, termed neurokinin (NK)(1), NK(2)and NK(3). In this study we characterized the receptor subtype responsible for the differential secretagogue effects in rat trachea by means of selective receptor antagonists and receptor agonists.SR 140333 [NK(1)-antagonist] completely inhibited SP action (283,29+/-21, 12%-->84,53+/-4, 09%; P<0,01) and significantly reduced the effects of NKA (179,08+/-17,34%-->118,86+/-6,7%; P<0,01) and NKB (171,89+/-5, 75%-->109,5+/-4,11%; P<0,01). SR 48968 [NK(2)-antagonist] did not affect SP action, but reduced the effects of NKA and NKB. SR 142801 [NK(3)-antagonist] did not change any effect of SP, NKA or NKB. [Sar(9)]SP (NK(1)-agonist) caused strong dose-dependent secretagogue effects similar to SP, [betaAla(8)]NKA (NK(2)-agonist) showed only slight and [Pro(7)]NKB (NK(3)-agonist) no effects. The present data suggest that the secretagogue effects elicited by tachykinins in rat trachea are mediated via NK(1)receptors.

[Cardiac arrhythmias in sleep apnea. Increased cardiovascular risk caused by nocturnal arrhythmia?]. / Herzrhythmusstörungen bei Schlafapnoe. Erhöhtes kardiovaskuläres Risiko durch nächtliche Arrhythmien?

In sleep-disordered breathing (SDB), the greatest clinical relevance attaches to obstructive sleep apnea on account of its high prevalence and its concomitance with diseases of the cardiovascular system. The high mortality rate of untreated patients is believed to be due to the consequences of these latter diseases. Thus, for example, in addition to systemic arterial hypertension, elevated rates of such disorders as pulmonary hypertension, right heart insufficiency, coronary heart disease, myocardial infarction and stroke are also found. Up until quite recently bradycardic and tachycardic arrhythmias occurring during sleep have been held responsible of the increased mortality rate of these patients. Till the mid-eighties the prevalence of bradycardic arrhythmias was reported to be more than 30%. However, the importance of cardiac arrhythmias has been overestimated, as is supported in particular by current studies on large non-selected samples showing a much lower prevalence of apnea-related arrhythmias. In the differential diagnosis, however, consideration must be given to SDB in patients with nocturnal arrhythmias and heart rate variations.

Effects of VIP and related peptides on airway mucus secretion from isolated rat trachea.

Vasoactive intestinal polypeptide (VIP) is known as an important regulator of airway function. It has been suggested that VIP is involved in the pathogenesis of asthma due to its relaxant effects on smooth muscles. The present study was designed to characterize the effects of the peptides of the VIP family on airway mucus secretion. The peptides VIP, PHI, PACAP-27, PACAP-38, GLP-I, exendin-4, helodermin, helospectin I and helospectin II were investigated using isolated rat trachea. Data show that PACAP-27 is the most potent stimulator of airway mucus secretion (225% stimulation). The rank order of potency was PACAP-27 > VIP > helospectin II > PHI > exendin-4 = helodermin = helospectin I = PACAP-38. The addition of the protease inhibitor thiorphan enhanced the effects of PHI and helodermin, but not of the other peptides. These data show that the peptides of the VIP family stimulate airway mucus secretion differently.

Effects of selective and non-selective phosphodiesterase inhibitors on tracheal mucus secretion in the rat.

The present study was designed to characterize the effects of unselective and isoenzyme-selective phosphodiesterase inhibitors on airway mucus secretion. The isolated rat trachea was incubated in a modified Ussing chamber. Mucus macromolecules were metabolically labelled with 35S. The inhibitors were applied at the luminal side. The unselective phosphodiesterase inhibitors theophylline, enprofylline and 3-isobutyl-methylxanthine stimulated mucus secretion in a concentration-dependent manner with half-maximum effects (EC50 values) at 690 microM, 400 microM and 46 microM, respectively. The adenosine antagonist 8-phenyltheophylline did not significantly stimulate mucus output, suggesting a negligible role of adenosine in the cellular mechanisms of mucus secretion. Adenosine itself did not increase radiolabel output. Rolipram, an inhibitor of phosphodiesterase isoenzyme IV, and zardaverine, which inhibits the isoenzymes III and IV, increased potently macromolecule output with EC50 values of 40 nM and 6 microM, respectively. The selective inhibitors of phosphodiesterase isoenzymes III and V, motapizone and zaprinast, did not influence airway mucus release, suggesting a relatively low activity of isoenzymes III and V in glands of rat trachea. The stimulatory effect of theophylline on airway mucus secretion may contribute to its beneficial action in chronic obstructive airway disease. Our data suggest that this effect is mediated predominantly by phosphodiesterase isoenzyme IV.

Galanin and somatostatin inhibition of neurokinin A and B induced airway mucus secretion in the rat.

Neurokinin A and B are present in neurons situated in lung and NK-1 receptors have been described on tracheal submucosal gland cells. In the present study we compared the ability of substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) to stimulate airway mucus secretion. Furthermore, we characterized the interaction of NKA and NKB with galanin and somatostatin. The rank order of the tachykinins to stimulate airway mucus secretion was SP > NKA > NKB suggesting that NK-1 receptors mediate these effects(EC50:SP: 50 nmol/l, NKA: 200 nmol/l, NKB: 400 nmol/l). Galanin and somatostatin were equally potent to inhibit NK-A and NK-B stimulated airway mucus release. These results suggest that NK-A and NK-B are potent stimulators of airway macromolecule secretion. Galanin and somatostatin potently inhibit these actions of the tachykinins. Therefore, airway mucus secretion is controlled by a complex network of several different mediators.

Galanin and somatostatin inhibition of substance P-induced airway mucus secretion in the rat.

Substance P is present in several neurons innervating the lung. Tachykinin receptors are expressed on submucosal gland cells. Substance P is known to be a potent stimulator of airway mucus secretion. In the present study we characterized the effects of galanin and somatostatin on basal and substance P-induced mucus secretion. The stimulatory effect of substance P was concentration-dependent (100 pmol/l: 112%, 1 nmol/l: 120%, 10 nmol/l: 153%, 100 nmol/l: 223%, 1 mumol/l: 275%, 10 mumol/l: 172%) and was inhibited by galanin and somatostatin (1 mumol/l substance P: 277%; 1 mumol/l substance P + 1 mumol/l somatostatin: 190%, p < 0.01; 1 mumol/l substance P + 1 mumol/l galanin: 206%, p < 0.05). In the presence of lower concentrations of substance P 1 mumol/l somatostatin and 1 mumol/l galanin did not modify mucus secretion. Lower concentrations of galanin and somatostatin did not significantly change mucus secretion stimulated by 1 mumol/l substance P. Both, galanin and somatostatin at 1 mumol/l left basal airway mucus secretion unaltered. These data suggest that mucus secretion into airways is regulated by a complex network of peptidergic stimulators and inhibitors including substance P, somatostatin and galanin.

Amylin immunoreactivity in the rat trachea and characterization of the interaction of amylin and somatostatin on airway mucus secretion.

Amylin is a peptide containing 37 amino acids that is mainly expressed in pancreatic B-cells and cosecreted with insulin. It is the major component of the islet amyloid typically found in non-insulin-dependent diabetes mellitus. The amylin mRNA is present in RNA isolated from lung, and amylin receptors have been detected in lung membranes. Recently, amylin was shown to be a potent stimulator of airway mucus secretion. In this study, we characterized the site of amylin expression in rat trachea using a highly specific antiserum and the functional interaction of amylin with somatostatin-14 in mucus secreting cells. Amylin-like immunoreactivity is present in epithelial cells of submucous gland acini. The expression pattern varies, since some acini showed strong staining while others were negative. In addition, some columnar cells of the tracheal lining epithelium are strongly stained. Amylin applied submucosally is a potent stimulator of airway mucus secretion. Somatostatin inhibits this effect. Amylin may influence airway mucus secretion by paracrine and endocrine mechanisms, and our data suggest that amylin and somatostatin belong to the increasing number of peptides that are known to influence airway function.