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: The bioavailability profiles of two sustained-release oral theophylline preparations , Respbid and Theo-Dur , were compared in 19 adults with obstructive airways disease .  Intravenous aminophylline  was used as the reference st and ard . No significant differences were detected in fraction absorbed , peak-trough fluctuations , or time to peak concentrations Theophylline is commonly prescribed for chronic obstructive pulmonary disease ( COPD ) , although controlled studies do not exist to support this use . We administered theophylline and placebo orally to 40 ambulatory COPD patients in a double-blind , crossover manner . Pulmonary function tests were conducted before and after isoproterenol nebulization on the final day of each four-week study period . Theophylline therapy produced small , but significant , increases over placebo in mean values . However , only the forced expiratory volume in 1 s was " improved , " according to published criteria . There were no significant differences in subjective effects between treatment periods . Six patients were identified as " responders " ; responder status could be predicted on the basis of improvement in flow rates after isoproterenol nebulization . Theophylline therapy is not beneficial to most COPD patients , and potential responders should be given carefully monitored therapeutic trials rather than arbitrarily being given maintenance therapy We studied ventilatory , hemodynamic , and subjective responses to different plasma theophylline concentrations in 10 patients with " irreversible " airflow obstruction . Subjects received theophylline at doses that produced low ( 9.0 to 12.5 micrograms/mL ) and high ( 17 to 22 micrograms/mL ) peak plasma concentrations ; subjects also received placebo . A significant ( P less than 0.05 ) dose-related difference in pulmonary function was observed between each treatment . The mean maximal increase in forced expiratory volume at 1 second over placebo was 21.3 % for high-dose theophylline and 6.0 % for low dose . Both treatments were well tolerated with respect to hemodynamic changes and other adverse effects . Despite improved findings in pulmonary function tests patients were unable to distinguish either treatment from placebo in terms of improvement in breathlessness BACKGROUND Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations .  Salmeterol and theophylline are indicated for the treatment of COPD , but the use of these agents in combination has not been extensively studied . OBJECTIVES To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD . METHODS R and omized , double-blind , double-dummy , parallel-group trial in 943 patients with COPD . After an open-label theophylline titration period ( serum levels , 10 to 20 microg/mL ) , patients were r and omly assigned to receive salmeterol ( 42 microg bid ) plus theophylline , salmeterol ( 42 microg bid ) , or theophylline for 12 weeks . Serial pulmonary function tests were completed on day 1 and treatment week 12 . Patients kept diary cards and noted their peak flow rates , symptom scores , and albuterol use , and periodically completed quality -of-life and dyspnea question naires . RESULTS All three groups significantly improved compared with baseline . Combination treatment with salmeterol plus theophylline provided significantly ( p < or = 0.045 ) greater improvements in pulmonary function ; significantly ( p < or = 0.048 ) greater decreases in symptoms , dyspnea , and albuterol use ; and significantly fewer COPD exacerbations ( p = 0.023 vs theophylline ) . In general , treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline . Salmeterol treatment was also associated with significantly fewer drug-related adverse events ( p < or = 0.042 ) than either treatment that included theophylline . The safety profile ( adverse events , vital signs , and ECG findings ) of the two treatments that included theophylline were similar . CONCLUSION Patients with COPD may benefit from combination treatment with salmeterol plus theophylline , without a result ing increase in adverse events or other adverse sequelae The acute ventilatory , cardiovascular and tremorogenic effect of a high oral dose of terbutaline ( 5 mg ) was compared with that of half the dose ( 2.5 mg ) combined with 280 mg anhydrous theophylline orally in a r and omized , double‐blind , cross‐over study in eight asthmatics . After 120 min . when steady‐state bronchodilation was achieved , five terbutaline inhalations ( 1.25 mg terbutaline sulphate ) were added to both treatment regimens . The mean maximum plasma concentration  of theophylline  was then 7 μg/ml ( 39 μmol/l ) BACKGROUND Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration ( periodic breathing ) . We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction . METHODS Fifteen men with compensated heart failure ( left ventricular ejection fraction , 45 percent or less ) participated in the study . Their base-line polysomnograms showed periodic breathing , with more than 10 episodes of apnea and hypopnea per hour . In a double-blind crossover study , the patients received theophylline or placebo orally twice daily for five days , with one week of washout between the two periods . RESULTS After five days of treatment , the mean ( + /-SD ) plasma theophylline concentration was 11 + /- 2 microgram per milliliter . Theophylline therapy result ed in significant decreases in the number of episodes of apnea and hypopnea per hour ( 18 + /- 17 , vs. 37 + /- 23 with placebo and 47 + /- 21 at base line ; P<0.001 ) , the number of episodes of central apnea per hour ( 6 + /- 14 , vs. 26 + /- 21 and 26 + /- 20 , respectively ; P<0.001 ) , and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent ( 6 + /- 11 percent , vs. , 23 + /- 37 and 14 + /- 14 percent , respectively ; P<0.04 ) . There were no significant differences in the characteristics of sleep , the frequency of ventricular arrhythmias , daytime arterial-blood gas values , or the left ventricular ejection fraction during the base-line , placebo , and theophylline phases of the study . CONCLUSIONS In patients with stable heart failure , oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep In two groups ( A and B ) of patients with severe chronic obstructive pulmonary disease ( COPD ) , matched for age and routine pulmonary function testing , we evaluated inspiratory muscle strength ( MIP ) , breathing pattern , mouth occlusion pressure ( P0.1 ) , inspiratory neural drive , assessed in terms of electromyographic activity of both diaphragm ( EMGd ) and intercostal ( EMGint ) muscles , and P0.1/EMGd ratio , an index of inspiratory neuromuscular coupling . Group A ( 8 patients ) was studied before and after a 7-day period of a new oral xanthine derivative ( bamiphylline , 1.2 g daily ) , and group B ( 7 patients ) was given a placebo . Under control conditions , compared with an age-matched normal control group , groups A and B both exhibited a decrease in MIP , more rapid ( increase in respiratory frequency RF ) and shallower ( decrease in tidal volume ; VT ) breathing ( RSB ) , a marked increase in both EMGd and EMGint and a lower P0.1/EMGd ratio . With bamiphylline  FEV1 and PaO2 significantly increased , while a substantial increase in MIP was found in 5 out of the 8 patients . VT and inspiratory time ( Ti ) also significantly increased , and RF decreased . Both EMGd and EMGint significantly decreased , whereas P0.1/EMGd exhibited a substantial increase in 5 out of the 8 patients . Conversely , no significant changes were observed in group B during the study period . From these data we conclude that in patients with COPD , clinical manifestations , probably associated with inspiratory muscle overloading ( decrease in muscle strength , RSB , increase in respiratory neural drive , and derangement in neuromuscular coupling ) may benefit from a short-term treatment with bamiphylline Twenty-four patients with reversible airflow obstruction under suboptimal control on conventional therapy entered a double-blind placebo-controlled trial of additional oral sustained release aminophylline . Assessment was by diary cards , twice daily PEFR , and weekly FEV1 .  Nineteen patients completed the trial satisfactorily . Eleven were improved subjectively by addition of aminophylline . The mean PEFR for all 19 patients rose from 232 1 min-1 SEM + /- 5 , to 247 1 min-1 SEM + /- 4 ( p less than 0.0001 ) ; nine individuals showed a statistically significant improvement in mean PEFR and 10 showed an improvement of greater than 200 ml in their FEV1 . Improvement in PEFR on aminophylline was not at the expense of benefit from inhaled salbutamol . Unwanted effects of nausea , headache , and abdominal discomfort were recorded by 12 of the 24 patients entering the trial . Seventeen of the 19 patients completing the trial had plasma theophylline levels in the accepted therapeutic range of 10 - 20 mg 1(-1 ) . The drug doses required to achieve these levels varied from 8.6 - 30.8 mg kg-1 24 hr-1 in the patients with no clinical or biochemical evidence of liver disease . Oral aminophylline can improve control of airflow obstruction in patients with moderately severe disease who are already receiving multiple medication , but side-effects often limit its use . The wide dose range required to achieve therapeutic plasma levels indicates that measurements of plasma theophylline are necessary for adequate interpretation of trials of theophylline compounds The bronchodilator , respiratory center and respiratory muscle effects of oral sustained release theophylline are investigated with a placebo controlled double-blind study in 34 patients with chronic obstructive lung disease ( COLD ) . The first 3 days were a theophylline washout period and the patients did not receive theophylline and on the 4th day , serum theophylline concentration was negligible . Initial pulmonary function tests were performed . Twenty-four of the patients took 350 mg oral sustained release theophylline twice a day . Ten of the patients were given placebo . On day 7 , serum theophylline concentrations of the study group were in therapeutic doses and the tests were repeated . Bronchodilator effect was assessed by spirometry , flow-volume loops and measuring airway resistance ( Raw ) . Respiratory muscle function was assessed by measuring maximal inspiratory ( PImax ) and expiratory pressures ( PEmax ) and the effect on respiratory center was evaluated by minute ventilation , mouth occlusion pressure index and inspiratory duty ratio . Forced vital capacity in one second ( p less than 0.001 ) , maximal mid expiratory flow rate ( p less than 0.05 ) , maximal expiratory flow at 50 percent of vital capacity ( p less than 0.001 ) , maximal inspiratory pressure ( p less than 0.01 ) increased , while airway resistance ( p less than 0.05 ) decreased significantly . Mouth occlusion pressure and minute ventilation mouth occlusion pressure index did not change after theophylline therapy . In placebo group , there was no significant change in airway obstruction assessed by spirometry and flow volume loops or in respiratory muscle function assessed by maximal respiratory pressures . It is therefore , concluded that oral sustained release theophylline has a bronchodilator effect in irreversible chronic obstructive lung disease , increases respiratory muscle function , but in therapeutic doses has no effect on respiratory center The effects of famotidine ( 80 mg per day ) , cimetidine ( 1600 mg per day ) , and placebo on theophylline  pharmacokinetic parameters in chronic obstructive pulmonary disease ( COPD ) patients were compared . This was an open-label , r and omized , three-period cross-over study , in which each subject first underwent a seven-day theophylline washout period , and thereafter received three single intravenous doses of theophylline ( 5 mg/kg infused over 30 minutes ) during the study . Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days ( 19 doses ) . Theophylline was infused after the 17th dose of each treatment . Fourteen serial blood sample s were collected before the start of each infusion , and for 30 hours after the end of each infusion . Plasma sample s were assayed for theophylline , pharmacokinetic parameters were estimated , and treatment effects on each parameter were compared . Fourteen COPD patients completed all three periods of the investigation . Famotidine treatment had virtually no effect on any of theophylline 's pharmacokinetic parameters . In contrast , cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows : Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h ( P < .00 
    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: The bioavailability profiles of two sustained-release oral theophylline preparations , Respbid and Theo-Dur , were compared in 19 adults with obstructive airways disease .  Intravenous aminophylline  was used as the reference st and ard . No significant differences were detected in fraction absorbed , peak-trough fluctuations , or time to peak concentrations Theophylline is commonly prescribed for chronic obstructive pulmonary disease ( COPD ) , although controlled studies do not exist to support this use . We administered theophylline and placebo orally to 40 ambulatory COPD patients in a double-blind , crossover manner . Pulmonary function tests were conducted before and after isoproterenol nebulization on the final day of each four-week study period . Theophylline therapy produced small , but significant , increases over placebo in mean values . However , only the forced expiratory volume in 1 s was " improved , " according to published criteria . There were no significant differences in subjective effects between treatment periods . Six patients were identified as " responders " ; responder status could be predicted on the basis of improvement in flow rates after isoproterenol nebulization . Theophylline therapy is not beneficial to most COPD patients , and potential responders should be given carefully monitored therapeutic trials rather than arbitrarily being given maintenance therapy We studied ventilatory , hemodynamic , and subjective responses to different plasma theophylline concentrations in 10 patients with " irreversible " airflow obstruction . Subjects received theophylline at doses that produced low ( 9.0 to 12.5 micrograms/mL ) and high ( 17 to 22 micrograms/mL ) peak plasma concentrations ; subjects also received placebo . A significant ( P less than 0.05 ) dose-related difference in pulmonary function was observed between each treatment . The mean maximal increase in forced expiratory volume at 1 second over placebo was 21.3 % for high-dose theophylline and 6.0 % for low dose . Both treatments were well tolerated with respect to hemodynamic changes and other adverse effects . Despite improved findings in pulmonary function tests patients were unable to distinguish either treatment from placebo in terms of improvement in breathlessness BACKGROUND Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations .  Salmeterol and theophylline are indicated for the treatment of COPD , but the use of these agents in combination has not been extensively studied . OBJECTIVES To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD . METHODS R and omized , double-blind , double-dummy , parallel-group trial in 943 patients with COPD . After an open-label theophylline titration period ( serum levels , 10 to 20 microg/mL ) , patients were r and omly assigned to receive salmeterol ( 42 microg bid ) plus theophylline , salmeterol ( 42 microg bid ) , or theophylline for 12 weeks . Serial pulmonary function tests were completed on day 1 and treatment week 12 . Patients kept diary cards and noted their peak flow rates , symptom scores , and albuterol use , and periodically completed quality -of-life and dyspnea question naires . RESULTS All three groups significantly improved compared with baseline . Combination treatment with salmeterol plus theophylline provided significantly ( p < or = 0.045 ) greater improvements in pulmonary function ; significantly ( p < or = 0.048 ) greater decreases in symptoms , dyspnea , and albuterol use ; and significantly fewer COPD exacerbations ( p = 0.023 vs theophylline ) . In general , treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline . Salmeterol treatment was also associated with significantly fewer drug-related adverse events ( p < or = 0.042 ) than either treatment that included theophylline . The safety profile ( adverse events , vital signs , and ECG findings ) of the two treatments that included theophylline were similar . CONCLUSION Patients with COPD may benefit from combination treatment with salmeterol plus theophylline , without a result ing increase in adverse events or other adverse sequelae The acute ventilatory , cardiovascular and tremorogenic effect of a high oral dose of terbutaline ( 5 mg ) was compared with that of half the dose ( 2.5 mg ) combined with 280 mg anhydrous theophylline orally in a r and omized , double‐blind , cross‐over study in eight asthmatics . After 120 min . when steady‐state bronchodilation was achieved , five terbutaline inhalations ( 1.25 mg terbutaline sulphate ) were added to both treatment regimens . The mean maximum plasma concentration  of theophylline  was then 7 μg/ml ( 39 μmol/l ) BACKGROUND Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration ( periodic breathing ) . We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction . METHODS Fifteen men with compensated heart failure ( left ventricular ejection fraction , 45 percent or less ) participated in the study . Their base-line polysomnograms showed periodic breathing , with more than 10 episodes of apnea and hypopnea per hour . In a double-blind crossover study , the patients received theophylline or placebo orally twice daily for five days , with one week of washout between the two periods . RESULTS After five days of treatment , the mean ( + /-SD ) plasma theophylline concentration was 11 + /- 2 microgram per milliliter . Theophylline therapy result ed in significant decreases in the number of episodes of apnea and hypopnea per hour ( 18 + /- 17 , vs. 37 + /- 23 with placebo and 47 + /- 21 at base line ; P<0.001 ) , the number of episodes of central apnea per hour ( 6 + /- 14 , vs. 26 + /- 21 and 26 + /- 20 , respectively ; P<0.001 ) , and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent ( 6 + /- 11 percent , vs. , 23 + /- 37 and 14 + /- 14 percent , respectively ; P<0.04 ) . There were no significant differences in the characteristics of sleep , the frequency of ventricular arrhythmias , daytime arterial-blood gas values , or the left ventricular ejection fraction during the base-line , placebo , and theophylline phases of the study . CONCLUSIONS In patients with stable heart failure , oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep In two groups ( A and B ) of patients with severe chronic obstructive pulmonary disease ( COPD ) , matched for age and routine pulmonary function testing , we evaluated inspiratory muscle strength ( MIP ) , breathing pattern , mouth occlusion pressure ( P0.1 ) , inspiratory neural drive , assessed in terms of electromyographic activity of both diaphragm ( EMGd ) and intercostal ( EMGint ) muscles , and P0.1/EMGd ratio , an index of inspiratory neuromuscular coupling . Group A ( 8 patients ) was studied before and after a 7-day period of a new oral xanthine derivative ( bamiphylline , 1.2 g daily ) , and group B ( 7 patients ) was given a placebo . Under control conditions , compared with an age-matched normal control group , groups A and B both exhibited a decrease in MIP , more rapid ( increase in respiratory frequency RF ) and shallower ( decrease in tidal volume ; VT ) breathing ( RSB ) , a marked increase in both EMGd and EMGint and a lower P0.1/EMGd ratio . With bamiphylline  FEV1 and PaO2 significantly increased , while a substantial increase in MIP was found in 5 out of the 8 patients . VT and inspiratory time ( Ti ) also significantly increased , and RF decreased . Both EMGd and EMGint significantly decreased , whereas P0.1/EMGd exhibited a substantial increase in 5 out of the 8 patients . Conversely , no significant changes were observed in group B during the study period . From these data we conclude that in patients with COPD , clinical manifestations , probably associated with inspiratory muscle overloading ( decrease in muscle strength , RSB , increase in respiratory neural drive , and derangement in neuromuscular coupling ) may benefit from a short-term treatment with bamiphylline Twenty-four patients with reversible airflow obstruction under suboptimal control on conventional therapy entered a double-blind placebo-controlled trial of additional oral sustained release aminophylline . Assessment was by diary cards , twice daily PEFR , and weekly FEV1 .  Nineteen patients completed the trial satisfactorily . Eleven were improved subjectively by addition of aminophylline . The mean PEFR for all 19 patients rose from 232 1 min-1 SEM + /- 5 , to 247 1 min-1 SEM + /- 4 ( p less than 0.0001 ) ; nine individuals showed a statistically significant improvement in mean PEFR and 10 showed an improvement of greater than 200 ml in their FEV1 . Improvement in PEFR on aminophylline was not at the expense of benefit from inhaled salbutamol . Unwanted effects of nausea , headache , and abdominal discomfort were recorded by 12 of the 24 patients entering the trial . Seventeen of the 19 patients completing the trial had plasma theophylline levels in the accepted therapeutic range of 10 - 20 mg 1(-1 ) . The drug doses required to achieve these levels varied from 8.6 - 30.8 mg kg-1 24 hr-1 in the patients with no clinical or biochemical evidence of liver disease . Oral aminophylline can improve control of airflow obstruction in patients with moderately severe disease who are already receiving multiple medication , but side-effects often limit its use . The wide dose range required to achieve therapeutic plasma levels indicates that measurements of plasma theophylline are necessary for adequate interpretation of trials of theophylline compounds The bronchodilator , respiratory center and respiratory muscle effects of oral sustained release theophylline are investigated with a placebo controlled double-blind study in 34 patients with chronic obstructive lung disease ( COLD ) . The first 3 days were a theophylline washout period and the patients did not receive theophylline and on the 4th day , serum theophylline concentration was negligible . Initial pulmonary function tests were performed . Twenty-four of the patients took 350 mg oral sustained release theophylline twice a day . Ten of the patients were given placebo . On day 7 , serum theophylline concentrations of the study group were in therapeutic doses and the tests were repeated . Bronchodilator effect was assessed by spirometry , flow-volume loops and measuring airway resistance ( Raw ) . Respiratory muscle function was assessed by measuring maximal inspiratory ( PImax ) and expiratory pressures ( PEmax ) and the effect on respiratory center was evaluated by minute ventilation , mouth occlusion pressure index and inspiratory duty ratio . Forced vital capacity in one second ( p less than 0.001 ) , maximal mid expiratory flow rate ( p less than 0.05 ) , maximal expiratory flow at 50 percent of vital capacity ( p less than 0.001 ) , maximal inspiratory pressure ( p less than 0.01 ) increased , while airway resistance ( p less than 0.05 ) decreased significantly . Mouth occlusion pressure and minute ventilation mouth occlusion pressure index did not change after theophylline therapy . In placebo group , there was no significant change in airway obstruction assessed by spirometry and flow volume loops or in respiratory muscle function assessed by maximal respiratory pressures . It is therefore , concluded that oral sustained release theophylline has a bronchodilator effect in irreversible chronic obstructive lung disease , increases respiratory muscle function , but in therapeutic doses has no effect on respiratory center The effects of famotidine ( 80 mg per day ) , cimetidine ( 1600 mg per day ) , and placebo on theophylline  pharmacokinetic parameters in chronic obstructive pulmonary disease ( COPD ) patients were compared . This was an open-label , r and omized , three-period cross-over study , in which each subject first underwent a seven-day theophylline washout period , and thereafter received three single intravenous doses of theophylline ( 5 mg/kg infused over 30 minutes ) during the study . Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days ( 19 doses ) . Theophylline was infused after the 17th dose of each treatment . Fourteen serial blood sample s were collected before the start of each infusion , and for 30 hours after the end of each infusion . Plasma sample s were assayed for theophylline , pharmacokinetic parameters were estimated , and treatment effects on each parameter were compared . Fourteen COPD patients completed all three periods of the investigation . Famotidine treatment had virtually no effect on any of theophylline 's pharmacokinetic parameters . In contrast , cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows : Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h ( P < .00 
    Output:
    