human
***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: Objective : Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor , which is mainly expressed on eosinophils . Eosinophils are key cells in the inflammatory cascade of various diseases , including asthma . This study investigated the pharmacokinetic (PK)/pharmacodynamic ( PD ) relationship between exposure of mepolizumab subcutaneous ( SC ) administration and blood eosinophil reduction compared with intravenous ( IV ) administration in adult subjects with asthma . Methods : In this multi-center , r and omized , open-label , parallel-group , repeat-dose study , 70 adult subjects received one of four possible treatment regimens : mepolizumab 12.5 , 125 , or 250 mg SC or 75 mg IV . In addition to analyzing the dose and PK/PD relationship , absolute bioavailability , safety , tolerability , and incidence of anti-mepolizumab antibodies were evaluated . Results : Blood eosinophil levels decreased in a dose-dependent manner with the lowest ( 12.5 mg ) dose clearly differentiating from the other doses . A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50 % and 90 % of maximal blood eosinophil inhibition were 11 mg ( 95 % confidence interval ( CI ) : 5.19 – 16.85 ) and 99 mg ( 95 % CI : 47 – 152 ) , respectively . The route of administration did not affect the exposure-response relationship . The estimated mepolizumab SC absolute bioavailability ( arm ) was 74 % ( 90 % CI : 54 – 102 % ) . The safety profile of mepolizumab was favorable . Conclusions : A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed . The subcutaneous absolute bioavailability was 74 % . The route of administration did not affect the mepolizumab exposure eosinophil response relationship RATIONALE The treatment effect of golimumab , a human monoclonal antibody against tumor necrosis factor (TNF)-alpha , in severe persistent asthma is unknown . OBJECTIVES To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled , severe persistent asthma . METHODS From 2004 to 2006 , 309 patients with severe and uncontrolled asthma , despite high-dose inhaled corticosteroids and long-acting beta(2 ) agonists , were r and omized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab ( 50 , 100 , or 200 mg ) through Week 52 . Co primary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1 ) and the number of severe asthma exacerbations through Week 24 . MEASUREMENTS AND MAIN RESULTS No significant differences were observed for the change in percent-predicted FEV1 ( least squares mean : placebo , 2.44 [ 95 % confidence interval ( CI ) -0.574 to 5.461 ] ; combined 100-mg and 200-mg , 2.91 [ 0.696 - 5.116 ] ) or severe exacerbations ( mean + /- SD : placebo , 0.5 + /- 1.07 vs. combined 100-mg and 200-mg 0.5 + /- 0.97 ) through week 24 . Through Week 24 , 2.6 % of patients treated with placebo vs. 19.5 % of those treated with golimumab discontinued the study agent , and 1.3 % and 7.8 % discontinued study participation , respectively . An unfavorable risk-benefit profile led to early discontinuation of study -agent administration after the Week-24 data base lock . Through Week 76 , 20.5 % of patients treated with placebo and 30.3 % of patients treated with golimumab experienced serious adverse events , with serious infections occurring more frequently in golimumab-treated patients . One death and all eight malignancies occurred in the active groups . CONCLUSIONS Overall , treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma . Clinical trial registered with www . clinical trials.gov ( NCT00207740 ) BACKGROUND IL-5 , a mediator of eosinophil activity , is an important potential treatment target in patients with uncontrolled asthma . The efficacy of reslizumab , a humanized anti-human IL-5 monoclonal antibody , has been characterized in patients with blood eosinophils ≥ 400 cells/μL. This study further characterizes the efficacy and safety of reslizumab in patients with poorly-controlled asthma , particularly those with eosinophils < 400 cells/μL. METHODS Patients were r and omly assigned to intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks . The primary end point was the change in FEV1 from baseline to week 16 . Secondary measures included Asthma Control Question naire-7 ( ACQ-7 ) scores , use of short-acting β-agonists ( SABAs ) , and FVC . RESULTS Four hundred ninety-two patients received ≥ 1 dose of placebo ( n = 97 ) or reslizumab ( n = 395 ) . In the overall population , mean FEV1 change from baseline to week 16 was not significantly different between reslizumab and placebo , and no significant relationship was detected between treatment , baseline blood eosinophils and change in FEV1 . In the subgroup of patients with baseline eosinophils < 400 cells/μL , patients treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo . In the subgroup with eosinophils ≥ 400 cells/μL , however , treatment with reslizumab was associated with much larger improvements in FEV1 , ACQ-7 , rescue SABA use , and FVC compared with the placebo group . Reslizumab was well tolerated , with fewer overall adverse events compared with placebo ( 55 % vs 73 % ) . CONCLUSIONS Reslizumab was well tolerated in patients with inadequately controlled asthma . Clinical ly meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01508936 ; URL : www . clinical trials.gov BACKGROUND Omalizumab , an anti-IgE monoclonal antibody , is administered by injection once or twice monthly in offices and clinics . It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy . OBJECTIVE To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine , a marker of allergic airway inflammation , and re source use . METHODS Patients ( N = 17 ) aged 6 to 26 years ( mean age , 16.4 years ) with poorly controlled persistent allergic asthma , less than 50 % adherence to inhaled corticosteroid therapy , a forced expiratory volume in 1 second ( FEV1 ) of 60 % predicted or higher , and adenosine provocation concentration that caused a decrease in FEV1 of 20 % ( PC20 ) of 60 mg/mL or less were r and omized to receive 4 months of omalizumab or placebo in a double-blind , crossover trial with a 3- to 4-month washout between treatments . Patients were instructed to continue taking inhaled corticosteroids throughout the study . The PC20 was measured before and after each period . RESULTS Fifteen patients completed the study . The mean baseline PC20 was 14.1 mg/mL ( 95 % CI , 10.8 - 18.4 mg/mL ) . The fold change PC20 was 0.9 ( 95 % CI , 0.5 - 1.7 ) during placebo and 3.1 ( 95 % CI , 1.6 - 6.2 ) during omalizumab treatment ; the estimated ratio was 3.4 ( 95 % CI , 1.2 - 9.3 ; P = .02 ) . Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo , but none required this intervention during omalizumab . During the study , the median prescription refills for inhaled corticosteroids was 0.15 ( 95 % CI , 0.00 - 0.33 ) canisters per month . CONCLUSION Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00133042 BACKGROUND AND OBJECTIVE There seems to be a strong causal relationship between allergy and the origins of asthma . Susceptibility to both is determined by a combination of genetics and environment acting through a complex network of cytokines . Nearly 90 % of affected children have positive skin tests indicating the presence of specific immunoglobulin E ( IgE ) , with sensitivity to house dust mite , Alternaria , cockroach , cat , and dog most closely linked to the disease . Greater exposure to house dust mite during infancy leads to earlier onset of wheezing , and elevated serum IgE levels correlate with the appearance of asthma symptoms . Specific IgE binds to high-affinity ( FcepsilonRI ) receptors on mast cells and basophils . The IgE-mediated reactions that follow exposure of sensitized mast cells to an allergen are design ated early- and late-phase asthmatic responses ( EAR and LAR ) . EAR is characterized by release of histamine and other preformed mediators within 1 hour of allergen exposure . It is often followed by LAR , an infiltration of the airways by inflammatory cells associated with an episode of more prolonged , and usually more severe airflow obstruction , 4 to 8 hours after antigen exposure . Chronic airway symptoms result from persistent LAR caused by continuous allergen exposure . IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity . IgE-mediated mast cell activation contributes to chronic tissue eosinophilia and airway remodeling , with permanent loss in pulmonary function .  Omalizumab ( rhuMAb-E25 ) is a recombinant , humanized , monoclonal anti-IgE antibody of mouse origin developed for the treatment of IgE-mediated diseases . Omalizumab binds to free IgE at the same site as the high-affinity receptor . Although it attaches to free IgE , it does not bind to IgA , IgG , or cell-bound IgE. It therefore does not induce cross-linking of cell-bound IgE , which would lead to the release of allergic mediators . It has been reported to decrease serum IgE levels in a dose-dependent manner , inhibit EAR and LAR , and cause a down-regulation of FcepsilonRI receptors on basophils . Omalizumab has been reported to be safe and effective in improving asthma control and reducing the requirement for oral and inhaled corticosteroids . This double-blind , r and omized , placebo-controlled study evaluated the safety , steroid-sparing effects , and impact on disease exacerbations of omalizumab in the treatment of childhood asthma . Methods . Participants were 334 males and premenarchal females aged 6 to 12 years , with moderate to severe allergic asthma requiring treatment with inhaled corticosteroids .  During a run-in phase , all children were switched to equivalent doses of beclomethasone dipropionate ( BDP ) , and the dose was adjusted to assure maintenance of asthma control achieved with previous corticosteroid treatment . Children were r and omized to subcutaneously administered placebo ( N = 109 ) or omalizumab ( N = 225 ) at a dose based on body weight and initial serum IgE ( 0.016 mg/kg/IgE [ IU/mL ] per 4 weeks ) . BDP dose ( initial range 168 - 420 microg/d ) was kept stable for 16 weeks ( stable-steroid phase ) , reduced over 8 weeks to the minimum effective dose ( steroid-reduction phase ) , and maintained constant for the final 4 weeks . RESULTS More participants in the omalizumab group decreased their BDP dose , and their reduction was greater than that of the placebo group ( median reduction 100 % vs 66.7 % ) . BDP was withdrawn completely in 55 % of the omalizumab group versus 39 % of the placebo group . The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the omalizumab group . The treatment differences were statistically significant during the steroid-reduction phase , during which fewer participants in the omalizumab group had asthma exacerbation episodes ( 18.2 % vs 38.5 % ) , and the mean number of episodes per patient was smaller than with placebo ( 0.42 vs 2.72 
    Output:
    
agent
***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: Objective : Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor , which is mainly expressed on eosinophils . Eosinophils are key cells in the inflammatory cascade of various diseases , including asthma . This study investigated the pharmacokinetic (PK)/pharmacodynamic ( PD ) relationship between exposure of mepolizumab subcutaneous ( SC ) administration and blood eosinophil reduction compared with intravenous ( IV ) administration in adult subjects with asthma . Methods : In this multi-center , r and omized , open-label , parallel-group , repeat-dose study , 70 adult subjects received one of four possible treatment regimens : mepolizumab 12.5 , 125 , or 250 mg SC or 75 mg IV . In addition to analyzing the dose and PK/PD relationship , absolute bioavailability , safety , tolerability , and incidence of anti-mepolizumab antibodies were evaluated . Results : Blood eosinophil levels decreased in a dose-dependent manner with the lowest ( 12.5 mg ) dose clearly differentiating from the other doses . A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50 % and 90 % of maximal blood eosinophil inhibition were 11 mg ( 95 % confidence interval ( CI ) : 5.19 – 16.85 ) and 99 mg ( 95 % CI : 47 – 152 ) , respectively . The route of administration did not affect the exposure-response relationship . The estimated mepolizumab SC absolute bioavailability ( arm ) was 74 % ( 90 % CI : 54 – 102 % ) . The safety profile of mepolizumab was favorable . Conclusions : A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed . The subcutaneous absolute bioavailability was 74 % . The route of administration did not affect the mepolizumab exposure eosinophil response relationship RATIONALE The treatment effect of golimumab , a human monoclonal antibody against tumor necrosis factor (TNF)-alpha , in severe persistent asthma is unknown . OBJECTIVES To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled , severe persistent asthma . METHODS From 2004 to 2006 , 309 patients with severe and uncontrolled asthma , despite high-dose inhaled corticosteroids and long-acting beta(2 ) agonists , were r and omized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab ( 50 , 100 , or 200 mg ) through Week 52 . Co primary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1 ) and the number of severe asthma exacerbations through Week 24 . MEASUREMENTS AND MAIN RESULTS No significant differences were observed for the change in percent-predicted FEV1 ( least squares mean : placebo , 2.44 [ 95 % confidence interval ( CI ) -0.574 to 5.461 ] ; combined 100-mg and 200-mg , 2.91 [ 0.696 - 5.116 ] ) or severe exacerbations ( mean + /- SD : placebo , 0.5 + /- 1.07 vs. combined 100-mg and 200-mg 0.5 + /- 0.97 ) through week 24 . Through Week 24 , 2.6 % of patients treated with placebo vs. 19.5 % of those treated with golimumab discontinued the study agent , and 1.3 % and 7.8 % discontinued study participation , respectively . An unfavorable risk-benefit profile led to early discontinuation of study -agent administration after the Week-24 data base lock . Through Week 76 , 20.5 % of patients treated with placebo and 30.3 % of patients treated with golimumab experienced serious adverse events , with serious infections occurring more frequently in golimumab-treated patients . One death and all eight malignancies occurred in the active groups . CONCLUSIONS Overall , treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma . Clinical trial registered with www . clinical trials.gov ( NCT00207740 ) BACKGROUND IL-5 , a mediator of eosinophil activity , is an important potential treatment target in patients with uncontrolled asthma . The efficacy of reslizumab , a humanized anti-human IL-5 monoclonal antibody , has been characterized in patients with blood eosinophils ≥ 400 cells/μL. This study further characterizes the efficacy and safety of reslizumab in patients with poorly-controlled asthma , particularly those with eosinophils < 400 cells/μL. METHODS Patients were r and omly assigned to intravenous reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks . The primary end point was the change in FEV1 from baseline to week 16 . Secondary measures included Asthma Control Question naire-7 ( ACQ-7 ) scores , use of short-acting β-agonists ( SABAs ) , and FVC . RESULTS Four hundred ninety-two patients received ≥ 1 dose of placebo ( n = 97 ) or reslizumab ( n = 395 ) . In the overall population , mean FEV1 change from baseline to week 16 was not significantly different between reslizumab and placebo , and no significant relationship was detected between treatment , baseline blood eosinophils and change in FEV1 . In the subgroup of patients with baseline eosinophils < 400 cells/μL , patients treated with reslizumab showed no significant improvement in FEV1 compared with those receiving placebo . In the subgroup with eosinophils ≥ 400 cells/μL , however , treatment with reslizumab was associated with much larger improvements in FEV1 , ACQ-7 , rescue SABA use , and FVC compared with the placebo group . Reslizumab was well tolerated , with fewer overall adverse events compared with placebo ( 55 % vs 73 % ) . CONCLUSIONS Reslizumab was well tolerated in patients with inadequately controlled asthma . Clinical ly meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01508936 ; URL : www . clinical trials.gov BACKGROUND Omalizumab , an anti-IgE monoclonal antibody , is administered by injection once or twice monthly in offices and clinics . It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy . OBJECTIVE To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine , a marker of allergic airway inflammation , and re source use . METHODS Patients ( N = 17 ) aged 6 to 26 years ( mean age , 16.4 years ) with poorly controlled persistent allergic asthma , less than 50 % adherence to inhaled corticosteroid therapy , a forced expiratory volume in 1 second ( FEV1 ) of 60 % predicted or higher , and adenosine provocation concentration that caused a decrease in FEV1 of 20 % ( PC20 ) of 60 mg/mL or less were r and omized to receive 4 months of omalizumab or placebo in a double-blind , crossover trial with a 3- to 4-month washout between treatments . Patients were instructed to continue taking inhaled corticosteroids throughout the study . The PC20 was measured before and after each period . RESULTS Fifteen patients completed the study . The mean baseline PC20 was 14.1 mg/mL ( 95 % CI , 10.8 - 18.4 mg/mL ) . The fold change PC20 was 0.9 ( 95 % CI , 0.5 - 1.7 ) during placebo and 3.1 ( 95 % CI , 1.6 - 6.2 ) during omalizumab treatment ; the estimated ratio was 3.4 ( 95 % CI , 1.2 - 9.3 ; P = .02 ) . Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo , but none required this intervention during omalizumab . During the study , the median prescription refills for inhaled corticosteroids was 0.15 ( 95 % CI , 0.00 - 0.33 ) canisters per month . CONCLUSION Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00133042 BACKGROUND AND OBJECTIVE There seems to be a strong causal relationship between allergy and the origins of asthma . Susceptibility to both is determined by a combination of genetics and environment acting through a complex network of cytokines . Nearly 90 % of affected children have positive skin tests indicating the presence of specific immunoglobulin E ( IgE ) , with sensitivity to house dust mite , Alternaria , cockroach , cat , and dog most closely linked to the disease . Greater exposure to house dust mite during infancy leads to earlier onset of wheezing , and elevated serum IgE levels correlate with the appearance of asthma symptoms . Specific IgE binds to high-affinity ( FcepsilonRI ) receptors on mast cells and basophils . The IgE-mediated reactions that follow exposure of sensitized mast cells to an allergen are design ated early- and late-phase asthmatic responses ( EAR and LAR ) . EAR is characterized by release of histamine and other preformed mediators within 1 hour of allergen exposure . It is often followed by LAR , an infiltration of the airways by inflammatory cells associated with an episode of more prolonged , and usually more severe airflow obstruction , 4 to 8 hours after antigen exposure . Chronic airway symptoms result from persistent LAR caused by continuous allergen exposure . IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity . IgE-mediated mast cell activation contributes to chronic tissue eosinophilia and airway remodeling , with permanent loss in pulmonary function .  Omalizumab ( rhuMAb-E25 ) is a recombinant , humanized , monoclonal anti-IgE antibody of mouse origin developed for the treatment of IgE-mediated diseases . Omalizumab binds to free IgE at the same site as the high-affinity receptor . Although it attaches to free IgE , it does not bind to IgA , IgG , or cell-bound IgE. It therefore does not induce cross-linking of cell-bound IgE , which would lead to the release of allergic mediators . It has been reported to decrease serum IgE levels in a dose-dependent manner , inhibit EAR and LAR , and cause a down-regulation of FcepsilonRI receptors on basophils . Omalizumab has been reported to be safe and effective in improving asthma control and reducing the requirement for oral and inhaled corticosteroids . This double-blind , r and omized , placebo-controlled study evaluated the safety , steroid-sparing effects , and impact on disease exacerbations of omalizumab in the treatment of childhood asthma . Methods . Participants were 334 males and premenarchal females aged 6 to 12 years , with moderate to severe allergic asthma requiring treatment with inhaled corticosteroids .  During a run-in phase , all children were switched to equivalent doses of beclomethasone dipropionate ( BDP ) , and the dose was adjusted to assure maintenance of asthma control achieved with previous corticosteroid treatment . Children were r and omized to subcutaneously administered placebo ( N = 109 ) or omalizumab ( N = 225 ) at a dose based on body weight and initial serum IgE ( 0.016 mg/kg/IgE [ IU/mL ] per 4 weeks ) . BDP dose ( initial range 168 - 420 microg/d ) was kept stable for 16 weeks ( stable-steroid phase ) , reduced over 8 weeks to the minimum effective dose ( steroid-reduction phase ) , and maintained constant for the final 4 weeks . RESULTS More participants in the omalizumab group decreased their BDP dose , and their reduction was greater than that of the placebo group ( median reduction 100 % vs 66.7 % ) . BDP was withdrawn completely in 55 % of the omalizumab group versus 39 % of the placebo group . The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the omalizumab group . The treatment differences were statistically significant during the steroid-reduction phase , during which fewer participants in the omalizumab group had asthma exacerbation episodes ( 18.2 % vs 38.5 % ) , and the mean number of episodes per patient was smaller than with placebo ( 0.42 vs 2.72 
    Output:
    