***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 r and omized 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 r and omization 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 st and ard 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 Clinical Trials.gov : NCT00073177 , NCT00076076 , NCT00163527 Background Inhaled allergen challenge is a st and ard method to study airway responses to inflammatory provocation and evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma .  MEM 1414 is a novel oral PDE4 inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDE inhibitors . We evaluated the tolerability and effect of MEM 1414 on airway responses in mild asthmatics . Methods A r and omised double blind placebo controlled cross over study in two centres , in which sixteen steroid naïve atopic asthmatics were challenged with inhaled allergen . Subjects were dosed with MEM 1414 ( 600 mg ) or placebo , twice daily orally for 7 days . Allergen challenge was performed on day 6 ( 2 hours post-dose ) , and methacholine responsiveness was measured 24 hours post allergen ( day 7 ) . Biomarkers of drug effects using ex vivo LPS stimulation of whole blood production of interleukin (IL)-6 and leukotriene (LT)-B4 and fractional exhaled nitric oxide ( FeNO ) were measured on day 6 ( 0 , 2 and 8 hours post-dose ) . Plasma pharmacokinetics were measured on days 1 , 6 and 7 . The primary endpoint was the effect on late asthmatic response to allergen . Results Treatment with MEM 1414 abrogated the late phase response with a mean difference in FEV1 ( LAR 3–10 hours ) of 104 ml ( 25 % ) vs placebo ( p < 0.005 ) , with no effect on the early response . Biomarker responses were also attenuated with MEM 1414 treatment with reductions in LPS-stimulated whole blood assays for TNFα at 8 hours ( p < 0.03 ) and LTB4 at 24 hours ( p = 0.0808 ) with no change in the IL-6 response . The MEM 1414 treatment phase was associated with higher incidence of nausea ( 6/16 MEM 1414 vs 2/16 placebo ) and vomiting ( 3/16 vs 0/16 placebo ) . Conclusions Oral MEM 1414 , a novel PDE4 inhibitor , significantly reduces the late response following inhaled allergen challenge . MEM 1414 also inhibited whole blood assays of cytokine production from inflammatory cells . MEM 1414 was associated with a typical adverse event profile of PDE4 inhibitors , namely nausea and vomiting although these were mild side effects . Trial registration numberCurrent controlled trials IS RCT N48047493 Asthma is an increasing health problem worldwide , but the long-term temporal pattern of clinical symptoms is not understood and predicting asthma episodes is not generally possible . We analyse the time series of peak expiratory flows , a st and ard measurement of airway function that has been assessed twice daily in a large asthmatic population during a long-term crossover clinical trial . Here we introduce an approach to predict the risk of worsening airflow obstruction by calculating the conditional probability that , given the current airway condition , a severe obstruction will occur within 30 days . We find that , compared with a placebo , a regular long-acting bronchodilator ( salmeterol ) that is widely used to improve asthma control decreases the risk of airway obstruction . Unexpectedly , however , a regular short-acting β2-agonist bronchodilator ( albuterol ) increases this risk . Furthermore , we find that the time series of peak expiratory flows show long-range correlations that change significantly with disease severity , approaching a r and om process with increased variability in the most severe cases . Using a nonlinear stochastic model , we show that both the increased variability and the loss of correlations augment the risk of unstable airway function . The characterization of fluctuations in airway function provides a quantitative basis for objective risk prediction of asthma episodes and for evaluating the effectiveness of therapy 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 design ed 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 Background 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 . Methods 25 subjects with mild allergic asthma were r and omized 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 . Results 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 . Conclusions 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.Trial Registration Clinical Trials.gov : Selective inhibitors of phosphodiesterase-4 ( PDE4 ) inhibit the hydrolysis of intracellular cAMP , which may result in bronchodilation and suppression of inflammation . We examined the effect of 1 week treatment with BAY 19 - 8004 ( 5 mg once daily ) , a novel orally administered PDE4 inhibitor , on trough FEV1 and markers of inflammation in induced sputum in patients with asthma or chronic obstructive pulmonary disease ( COPD ) . Seven patients with asthma ( mean [ SD ] FEV1 69.5 [9.3]% predicted ; reversibility in FEV1 26.2 [10.1]% ; all non-smokers ) and 11 patients with COPD ( FEV1 58.6 [8.3]% predicted ; reversibility in FEV1 6.5 [4.7]% ; median [ range ] 44 [ 21 - 90 ] pack years of smoking ) were included in this r and omized , double-blind , placebo-controlled trial . FEV1 was measured before and after 1 week of treatment ; sputum was induced by 4.5 % saline inhalation on the last day of treatment . FEV1 did not improve during either treatment in both patient groups ( p>0.2 ) . Sputum cell counts were not different following placebo and BAY 19 - 8004 treatment in asthma and COPD patients ( p>0.2 ) . However , only in patients with COPD , small but significant reductions in sputum levels of albumin and eosinophil cationic protein were observed ( p<0.05 ) . In conclusion , 1 week of treatment with the selective PDE4 inhibitor BAY 19 - 8004 does not affect FEV1 and sputum cell numbers in patients with asthma or COPD . However , such treatment does seem to reduce levels of albumin and eosinophil cationic protein in sputum sample s obtained from patients with COPD Roflumilast is approved as an add-on therapy for chronic obstructive pulmonary disease . The inflammation in chronic obstructive pulmonary disease is mainly neutrophilic , while in asthma it is mainly eosinophilic , studies addressing role of roflumilast in eosinophilic inflammation are recommended . Also in severe asthma , the dominant inflammatory cells are neutrophils . Thus , roflumilast has a potential off-label use in the treatment of asthma . This study was design ed to evaluate the effects of co-inhalation of roflumilast and fluticasone compared to that of formoterol and fluticasone in ovalbumin-sensitized and -challenged BALB/c mice . Besides normal control group , the ovalbumin-asthmatic mice were r and omly divided into seven groups ( n = 8) : positive control , vehicle-treated , and five drug-treated groups . Treatments ( µg/kg ) were given as 15 min-inhalation once/day for five days as follows : roflumilast ( 500 ) , formoterol ( 50 ) , fluticasone ( 1000 ) , roflumilast + fluticasone ( 500 + 1000 ) , and formoterol + fluticasone ( 50 + 1 
    Output:
    
In patients with mild asthma , oral PDE4 inhibitors can be considered as an alternative treatment to regular bronchodilators and inhaled controllers