Comparison of two sustained-release theophylline preparations in adult patients with obstructive airways disease. Treatment of chronic obstructive pulmonary disease with orally administered theophylline. A double-blind, controlled study. Efficacy of theophylline in "irreversible" airflow obstruction. Salmeterol plus theophylline combination therapy in the treatment of COPD. Effects of Oral Theophylline Combined with Oral and Inhaled β2‐Adrenostimulants in Asthmatics Effect of theophylline on sleep-disordered breathing in heart failure. Control of breathing in patients with chronic pulmonary obstructive disease: response to bamiphylline. Sustained release oral aminophylline in patients with airflow obstruction. Effect of theophylline in chronic obstructive lung disease. Controlled study of the putative interaction between famotidine and theophylline in patients with chronic obstructive pulmonary disease. Treatment of patients with chronic airways obstruction: a controlled study with bamyphylline. Arrhythmogenicity from combined bronchodilator therapy in patients with obstructive lung disease and concomitant ischemic heart disease. The Usefulness of Theophylline in Nonasthmatic Airway Obstruction The effects of theophylline and salbutamol on right and left ventricular function in chronic bronchitis and emphysema. Acute response to bronchodilator. An imperfect guide for bronchodilator therapy in chronic airflow limitation. Should study subjects see their previous responses: data from a randomized control trial. The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD. The combined effect of theophylline and terbutaline in patients with chronic obstructive airway diseases. Sleep quality and nocturnal respiratory function with once-daily theophylline (Uniphyl) and inhaled salbutamol in patients with COPD. Dose response relation to oral theophylline in severe chronic obstructive airways disease. Steroid response in stable chronic obstructive pulmonary disease. Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive pulmonary disease. Effect of theophylline on exercise performance in patients with severe chronic obstructive pulmonary disease. Physiological and neuropsychological effects of theophylline in chronic obstructive pulmonary disease. Theophylline clearance in patients with severe chronic obstructive pulmonary disease receiving supplemental oxygen and the effect of acute hypoxemia. [The effect of an oral aminophylline compound with protracted activity on respiratory resistance and blood gases in obstructive respiratory diseases (author's transl)]. A comparison of enprofylline and theophylline in the maintenance therapy of chronic reversible obstructive airway disease. Effect of oral salbutamol and slow-release aminophylline on exercise tolerance in chronic bronchitis. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. [Euphylong in standard dosage: comparison with an international retard preparation for twice-daily administration in recommended dosage]. Suppression of Airway Inflammation by Theophylline in Adult Bronchial Asthma Randomised controlled trial of aminophylline for severe acute asthma Effects of high-dose ipratropium bromide and oral aminophylline on spirometry and exercise tolerance in COPD. Nedocromil sodium versus theophylline in the treatment of reversible obstructive airway disease. The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A double-blind single dose study. Does inhaled albuterol improve diaphragmatic contractility in patients with chronic obstructive pulmonary disease? Effect of theophylline on sleep and sleep-disordered breathing in patients with chronic obstructive pulmonary disease. Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects. Treatment of reversible chronic airways obstruction with doxofylline compared with slow-release theophylline: a double-blind, randomized, multicentre trial. Theophylline improves measurements of respiratory muscle efficiency. Effect of theophylline on erythrocytosis in chronic obstructive pulmonary disease. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. Sustained-release theophylline reduces dyspnea in nonreversible obstructive airway disease. The efficacy of isoproterenol inhalation for predicting the response to orally administered theophylline in chronic obstructive pulmonary disease. Theophylline and salbutamol in combination in patients with obstructive pulmonary disease and concurrent heart disease: effect on cardiac arrhythmias. The effects of doxofylline versus theophylline on sleep architecture in COPD patients. Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease Salmeterol versus slow-release theophylline in patients with reversible obstructive pulmonary disease. Theophylline and salbutamol improve pulmonary function in patients with irreversible chronic obstructive pulmonary disease. Physiologic effects of oral bronchodilators during rest and exercise in chronic obstructive pulmonary disease. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. The effect of theophylline on respiratory muscle contractility and fatigue. Effect of theophylline on airway inflammation in asthma. Overnight theophylline concentrations and effects on sleep and lung function in chronic obstructive pulmonary disease. Isoproterenol challenge during placebo and oral theophylline therapy in chronic obstructive pulmonary disease. Oral doxophylline in patients with chronic obstructive pulmonary disease. The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction. Controlled Release Salbutamol Tablets versus Sustained Release Theophylline Tablets in the Control of Reversible Obstructive Airways Disease Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. [Nedocromil sodium therapy in asthma patients. Therapeutic effect in addition to treatment with oral theophylline and inhaled bronchodilator agents]. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects. A novel bronchodilator xanthine apparently without adenosine receptor antagonism and tremorogenic effect. Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease. Assessment of combined oral theophylline and inhaled beta-adrenoceptor agonist bronchodilator therapy. Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice. Sustained-release theophylline in chronic bronchitis. A Single-Blind Crossover Study of Two Different Slow Release Theophylline Preparations Comparative assessment of enprofylline and theophylline for chronic obstructive airways disease in the elderly. Aminophylline, respiratory muscle strength and exercise tolerance in chronic obstructive airway disease. Aminophylline therapy for acute bronchospastic disease in the emergency room. Effect of aminophylline on exercise performance in patients with irreversible airway obstruction. Is oral theophylline effective in combination with both inhaled anticholinergic agent and inhaled beta 2-agonist in the treatment of stable COPD? Safety and efficacy of once-daily Uniphyl tablets compared with twice-daily Theo-Dur tablets in elderly patients with chronic airflow obstruction. A comparison of inhaled ipratropium, oral theophylline plus inhaled beta-agonist, and the combination of all three in patients with COPD. Rational intravenous doses of theophylline. Dyspnea and diaphragmatic fatigue in patients with chronic obstructive pulmonary disease. Responses to theophylline. Effects of theophylline on respiratory drive in patients with chronic obstructive pulmonary disease. [Theophylline treatment of irreversible, chronic obstructive pulmonary disease].
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 < .001 ) , and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours ( P < .001 ) and mean residence time from 10.8 to 15.0 hours ( P < .001 ) . Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10 % , and that change also was statistically significant ( P = .032 ) . The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others , and that famotidine treatment had no effect on any of theophylline 's pharmacokinetic parameters in COPD patients A single-blind , placebo-controlled study was carried out in 30 patients with chronic obstructive bronchopneumopathy to assess the effectiveness and tolerability of the theophylline derivative , bamyphylline . On entry , patients were allocated to receive twice daily oral doses of either 600 mg bamyphylline or placebo for a period of 60 days . Spirometric measurements , blood pressure and respiratory rate recordings and blood gas analyses were made at baseline and after 10 , 30 and 60 days of treatment , as were assessment s of clinical and objective signs , such as sibili , rales and vesicular murmurs . Plasma concentrations of bamyphylline 1 hour after the first dose of the day were monitored at the same intervals . The results showed that there was a highly significant progressive improvement in pulmonary function which was already apparent after 10 days and this was accompanied by a marked improvement in cardiac dynamics and clinical signs . Plasma concentrations of bamyphylline  remained stable throughout the study period and there were no reports of side-effects or significant variations in blood chemistry Twenty-four patients ( five women ) aged 53 - 72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline ( 600 mg daily ) , enprofylline ( 600 mg daily ) or placebo . The study was double-blind , r and omized , triple-crossover with each regimen given for two weeks . Holter monitoring was used during 48 consecutive hours in each period . Compared with placebo , addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm ( p less than 0.001 ) . A small , but statistically significant ( p less than 0.05 ) increase in mean hourly frequency of premature ventricular beats ( PVBs ) occurred with enprofylline as compared with placebo . However , in only two patients with enprofylline ( and one patient with theophylline ) the increase in PVBs was such that a clinical ly relevant proarrhythmic effect seems possible . Furthermore , ventricular tachycardia was not more frequently observed with any xanthine than with placebo . Thus , combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease . Holter monitoring is recommended to assess the individual patient 's response to such therapy This study evaluated the effectiveness of oral bronchodilator therapy using theophylline in patients with nonreversible chronic obstructive pulmonary dis ease . Twelve chronic obstructive pulmonary disease patients were entered into a doubleblind crossover study using either active drug theophylline in 200 mg capsules ( Elixophyllin ) or placebo for 3 months , followed by 3 months of the alternate capsule . At baseline and monthly visits , data were recorded , including history , physical examination , and pulmonary function testing . Clinical ly , 7 of 11 patients responded favorably to theophylline , 3 were unchanged , and 1 improved on placebo . Comparison of each sign and symptom individually revealed no statistically significant differences . Pulmonary function ( FEV1 and FVC ) showed slight deterioration with placebo , but not with active drug therapy . These findings suggest that nonasthmatic patients may improve clinical ly during theophylline therapy whereas their pulmonary function may deteriorate during placebo therapy We have compared the effects of oral theophylline and salbutamol on right and left ventricular function in twelve patients with chronic bronchitis and emphysema .  Right and left ventricular ejection fraction ( RVEF and LVEF ) were measured using multiple gated radionuclide ventriculography . Theophylline 600 mg and salbutamol 4 mg both produced increases in RVEF and LVEF . There were no significant changes in blood gases after either drug . The clinical significance of the effects of oral bronchodilators on cardiac function in patients with chronic bronchitis and emphysema has yet to be determined We conducted a four-period cross-over r and omized trial in which we found that patients with chronic airflow limitation demonstrated symptomatic improvement with both inhaled albuterol and oral theophylline . The response , however , was not uniform . We therefore tested the ability of acute change in forced expired volume in one second ( FEV1 ) following inhaled beta agonist to predict long-term symptomatic response to albuterol and theophylline . We found that the reproducibility of acute change in FEV1 over three repetitions was poor ( intraclass correlation 0.17 ) . Furthermore , the mean improvement FEV1 following inhaled albuterol across the three repetitions did not relate closely to symptomatic response to either albuterol or theophylline . We conclude that acute response to inhaled beta agonist is not useful for identifying patients with chronic airflow limitation who are likely to benefit from bronchodilator treatment To test the relative merits of administering question naires with previous responses available ( the informed condition ) or unavailable ( the blind condition ) , we administered blind and informed versions of a quality of life question naire ( the Chronic Respiratory Disease Question naire , or CRQ ) in a r and omized , double-blind trial of bronchodilators in chronic airflow limitation . The responsiveness of the two methods , as reflected in the p-values associated with salbutamol and theophylline effects were comparable for three of the four dimensions of the CRQ . The data suggested possible increased responsiveness of the informed method for the emotional function dimension of the question naire . Changes in the informed CRQ dyspnea and fatigue dimensions showed stronger correlations with changes in spirometry , 6 minute walk distance , and rating of dyspnea after the walk test than did blind administration . Further , changes in all four CRQ dimensions showed stronger correlations with corresponding global ratings using the informed question naire . These results suggest that by letting study subjects see their previous responses the validity of subjective measures of health status in clinical trials can be improved STUDY OBJECTIVE To determine the additive effect of oral theophylline in patients with stable COPD who received both inhaled salbutamol , 400 micrograms , and ipratropium bromide , 80 micrograms , four times daily administered with a metered-dose inhaler . DESIGN Twenty-four male patients with stable COPD ( FEV1 , 0.96 + /- 0.43 L ; 36.8 + /- 17.0 percent predicted [ % pred ] ) completed a r and omized , double-blind , placebo-controlled crossover trial with oral theophylline for 4 weeks . MEASUREMENTS AND RESULTS The average serum theophylline level was 15.0 + /- 5.5 micrograms/mL during treatment . On the whole , without inhalation of bronchodilators , FEV1 was 0.93 + /- 0.42 L during the placebo period and 1.00 + /- 0.43 L ( significantly different from placebo ; p < 0.01 ) during the theophylline period . At 15 and 60 min after inhalation of salbutamol , 400 micrograms , and ipratropium , 80 micrograms , the FEV1 with placebo was 1.12 + /- 0.43 L and 1.14 + /- 0.46 L , respectively , and the FEV1 with theophylline was 1.18 + /- 0.45 L ( p < 0.01 ) and 1.20 + /- 0.47 L ( p < 0.01 ) , respectively . Daily peak expiratory flow rate also improved . Daily symptom scores were not significantly different between theophylline and placebo periods . Nevertheless , eight patients reported a subjective benefit during the theophylline administration period , and they were thus considered subjective responders . While FEV1 after inhalation was significantly improved during the theophylline periods in subjective responders ( change in FEV1 between theophylline and placebo treatment 15 min after inhalation , 3.1 % pred ; 60 min , 3.5 % pred ) , postbronchodilator FEV1 was not significantly different between the placebo and theophylline periods in subjective nonresponders ( 15 min , 1.7 % pred ; 60 min , 1.6 % pred ) . CONCLUSIONS On the whole , theophylline has a small bronchodilating effect but does not improve the symptoms of patients with stable COPD . However , one third of patients with COPD may respond subjectively to theophylline . The additive bronchodilating effect of theophylline may be related to the symptomatic improvement in subjective responders Using a double-blind , cross-over design the acute bronchodilating effect of 375 mg microcrystalline theophylline , 5 mg terbutaline , a combination of both drugs and placebo was studied in 11 patients suffering from moderate to severe chronic obstructive lung disease with partially reversible airway obstruction . Plasma concentrations both theophylline and terbutaline were measured . The bronchodilation produced by oral intake of 5 mg terbutaline and 375 mg theophylline was comparable . The maximal median value of terbutaline in plasma was 4.6 ng/ml 2 h after intake of medication , followed by a decline with a double peak in some patients . The maximal median increase of FEV1 was 37 % 3 h after intake of medication . The maximal median plasma level of theophylline  reached 12.5 ng/ml 30 min after intake of the medication . The median maximal increase of FEV1 was 24 % . One hour after intake of medication and throughout the whole test period up to 7 h , the combination of 5 mg terbutaline and 375 mg theophylline produced a significantly greater bronchodilation than each drug alone . It is concluded that 375 mg microcrystalline theophylline produced a significantly greater bronchodilation than each drug alone . It is concluded that 375 mg microcrystalline theophylline and 5 mg terbutaline produces almost equal bronchodilating activity : a combination of both drugs , however , results in further bronchodilation We compared the effects of evening administration of sustained-release theophylline ( Uniphyl ) and qid inhaled beta 2-agonist ( salbutamol , two 100-micrograms puffs ) on sleep quality and nocturnal oxygen saturation in 20 patients with COPD . Patients with FEV1 less than 70 % predicted and FEV1/FVC ratio less than 70 % were eligible to participate in this double-blind , crossover study , with 2-week treatment arms . Patients recorded morning and evening peak flow and symptoms in a daily diary . On the last day of each treatment period ,  overnight polysomnography  was done . Spirometric indexes were measured before retiring and on awakening . Patients spent less time at less than 90 % oxygen saturation ( 51 + /- 92 min vs 72 + /- 105 min ; p = 0.03 ) during theophylline treatments than during salbutamol treatment . There was a smaller overnight decrease in FEV1 ( 0.04 L vs 0.13 L ; p = 0.04 ) after theophylline than after sallbutamol treatment . FEV1/FVC ratio and maximum expiratory flow at 50 % of vital capacity ( V50 ) increased overnight with theophylline and decreased with salbutamol ( p = 0.014 , 0.025 ) . Morning peak expiratory flow rate was higher with theophylline ( 4.0 + /- 1.7 L/s ) than with salbutamol ( 3.6 + /- 1.8 L/s ; p = 0.004 ) . The duration of patient-reported nocturnal wheezing was lower with theophylline than with salbutamol ( p = 0.006 ) . There were no differences between treatments in sleep quantity , efficiency , staging , or subjective quality . We conclude that , compared with salbutamol , evening administration of once-daily theophylline results in better nocturnal oxygen saturation and an improvement in the overnight change in pulmonary function , without affecting sleep architecture , in patients with COPD OBJECTIVE --To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline .  DESIGN -- Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data . This was followed by r and om assignment to four consecutive two month treatment periods -- placebo and low , medium , and high dose , as assessed by serum concentrations of theophylline .  Respiratory function and exercise performance was assessed at the end of each two month period . SETTING --Chest unit in district hospital . PATIENTS --Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited ; 33 aged 53 - 73 years completed the study . INTERVENTIONS --Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted , when 400 mg was given . Targets for the steady state serum theophylline concentrations were 5 - 10 mg/l in the low dose period , 10 - 15 mg/l in the medium dose , and 15 - 20 mg/l in the high dose period . ENDPOINTS -- Respiratory function as measured by forced expiratory volume in one second , forced vital capacity , peak expiratory flow rate , slow vital capacity , and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived . Exercise performance assessed by six minute walking test and diary cards using visual analogue scale . MEASUREMENTS AND MAIN RESULTS --The forced expiratory volume in one second , forced vital capacity , and peak expiratory flow rate changed only slightly ( about 13 % ) over the range of doses . There was a linear dose dependent fall of trapped gas volume from 1.84 l ( SE 0.157 ) to 1.42 l ( 0.152 ) , 1.05 l ( 0.128 ) , and 0.67 l ( 0.102 ) during the placebo and low , medium , and high dose treatment periods . Mean walking distance increased by up to 55.6 m ( 20 % ) . There was a modest improvement in dyspnoea as the dose of theophylline was increased . Side effects were mostly minor but they became more frequent as the dose was increased . CONCLUSION --The fall in trapped gas volume may reflect an improvement in peripheral ventilation ( associated with treatment with theophylline ) which is less apparent in the more common tests of lung function used in patients with chronic obstructive airways disease We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease .  Placebo and steroid trials were separated by 2 weeks when no tablets were given . Response was assessed by measuring forced expiratory volume in 1 second ( FEV1.0 ) .  Placebo responses were normally distributed ( mean , 0.8 % change in FEV1.0 ; range , -30 % to 33 % ) . Six patients showed a greater than 50 % increase of FEV1.0 in response to steroid ; a seventh showed a 36 % increase and an eighth , a 29 % increase . Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo . The eight steroid responders did not differ from nonresponders in age , sex , smoking history , or duration and intensity of symptoms including wheeze . Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups . Patients who responded to steroids also responded to inhaled beta agonists : Acute bronchodilator response averaged 25 % in steroid responders and 13 % in nonresponders , a difference that was statistically significant although there was overlap between the two groups Partial bronchodilator reversibility can be demonstrated in many patients with stable chronic obstructive pulmonary disease ( COPD ) , but its relevance to exercise capacity and symptoms is uncertain . Previous data suggest that anticholinergic bronchodilators do not improve exercise tolerance in such patients . We studied 32 patients with stable COPD , mean age 65 yrs , in a double-blind , placebo-controlled , cross-over trial of the inhaled anticholinergic drug , oxitropium bromide . From the within and between day placebo spirometry , we derived the spontaneous variation in forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) of this population ( FEV1 140 ml ; FVC 390 ml ) and considered responses beyond this to be significant . Oxitropium bromide increased baseline FEV1 from 0.70 ( 0.28 ) l ( mean ( SD ) ) to 0.88 ( 0.36 ) l. The 6 min walking distance increased by 7 % compared with placebo , whilst resting breathlessness scores fell from 2.0 to 1.23 at rest and 4.09 to 3.28 at the end of exercise after the active drug . Improvements in walking distances and symptoms were unrelated to changes in either FEV1 or FVC , indicating that routine reversibility testing is not a good predictor of symptomatic benefit in these patients BACKGROUND --Theophylline is a well known bronchodilator which has been used for more than 50 years in the treatment of obstructive pulmonary diseases . In patients with severe chronic obstructive pulmonary disease whose cardiopulmonary performance is limited by their ventilatory capacity the administration of theophylline may improve exercise performance . METHODS --A r and omised , placebo controlled , double blind , crossover trial was conducted in 22 patients with severe but stable disease . The patients ( mean age 68 years ) were studied before and after one month of placebo and one month of treatment with a sustained release preparation of theophylline administered orally . The theophylline dose was adjusted until a blood level above 55.5 mumol/l was achieved . The two treatments were administered in r and om order and separated by a two week washout period . After theophylline was administered for one month a mean level of 68.2 mumol/l was achieved . Pulmonary function tests , arterial blood gas measurements , maximal voluntary ventilation ( MVV ) , and an incremental exercise test were performed before ( baseline ) and at the end of the first and second month of treatment . RESULTS --Pulmonary function tests showed no improvement in the flow parameters but showed an improvement in MVV after treatment with theophylline .  Pulmonary gas exchange was improved after theophylline ( resting arterial PO2 8.91 v 8.59 kPa , PCO2 5.38 v 5.56 kPa ) . The incremental exercise study showed improvement in maximal work rate ( 86.5 v 75.0 watts ) and maximal ventilation ( VEmax ) ( 46.7 v 43.01/min ) . The dyspnoea index on maximal effort ( VEmax/MVV ) , anaerobic threshold , and oxygen pulse remained unchanged . Resting and exercise heart rate were higher after theophylline . CONCLUSIONS --Theophylline improved cardiorespiratory performance in these patients with severe chronic obstructive pulmonary disease mainly by increasing the ventilatory capacity The effect of oral theophylline on clinical course , exercise , neuropsychological performance and bronchial reactivity was studied in chronic airflow obstruction . Twelve patients with chronic obstructive pulmonary disease ( COPD ) [ mean age 62.4 + /- 1.6 years ( SE ) , and forced expiratory volume in 1 sec of 1.15 + /- 0.1 l ] were r and omized to 4 weeks treatment with oral theophylline followed by 4 weeks of placebo , in a double-blind fashion . During each period , patients underwent clinical evaluation , incremental exercise  , a battery of neuropsychological tests measuring a wide range of cognitive functions , and an  inhaled methacholine provocation . On the active drug ( levels 9.5 + /- 1 mg/l ) , vital capacity and maximal breathing capacity were 16 + /- 7 % and 20 + /- 7 % respectively , higher relative to placebo ( P < 0.04 ) . Exercise capacity , as reflected by peak O2 uptake and the anaerobic threshold , improved 14 + /- 5 % and 18 + /- 5 % ( P < 0.04 ) . In contrast , bronchial responsiveness to inhaled methacholine and the mean scores on the neuropsychological tests were not significantly altered by the drug . Clinical symptoms were unaltered , but mild side effects were more common on theophylline . We concluded that in moderate to severe COPD , theophylline treatment , at the low range of the therapeutic dose , improves lung function and exercise capacity . This improvement is achieved with no detectable alteration of bronchial reactivity to methacholine and with no deleterious effect on cognitive functions The effect of hypoxemia on the disposition of theophylline was examined in 10 stable patients with chronic obstructive pulmonary disease ( COPD ) receiving chronic theophylline and supplemental home oxygen therapy .  Pharmacokinetics after  intravenous theophylline were estimated on the second day of supplemental oxygen ( PaO2 , 69 + /- 4 mmHg ; mean + /- SEM ) and on the second day of room air breathing ( PaO2 , 43 + /- 3 ) using a r and omized cross-over design . On each occasion stable isotope-enriched theophylline ( 10 mg , m/z 183 ) was administered intravenously along with the regular oral dose of theophylline ( m/z 180 ) . Concentrations of both forms of theophylline in plasma sample s obtained over 24 h were measured using mass spectrometry . Theophylline clearance during oxygen therapy ( 0.048 + /- 0.005 L/h/kg ) was similar to that during room air breathing ( 0.050 + /- 0.004 L/h/kg ) . Values for elimination half-life ( 7.6 + /- 0.8 versus 6.8 + /- 0.6 h ) and volume of distribution at steady state ( 0.450 + /- 0.021 versus 0.429 + /- 0.024 L/kg ) were also unchanged . The volume of distribution of theophylline was inversely related to arterial pH during oxygen therapy ( pH range , 7.32 to 7.44 ) and during room air breathing ( pH range , 7.33 to 7.47 ) . Although hypoxemia does not alter theophylline clearance in patients with COPD , theophylline loading doses may need adjustment according to arterial pH because of an effect on volume of distribution The effect of theophylline ethylenediamine oblong tablets ( Euphyllin retard ) was tested in 40 patients by means of a double-blind trial , applying a dose of 2 X 350 mg/d and 2 X 700 mg/d . At the dose of 2 X 700 mg/d Euphyllin retard showed a good bronchodilatory effect . A reduction of the obstruction in the airways and an improvement of the arterial blood gases was statistically secured . At the dose of 2 X 350 mg/d a sufficient bronchodilation could not be recorded To compare the efficacy and side effects of two xanthine derivatives in the maintenance therapy of reversible obstructive airway disease , 242 patients were assigned in r and omized , double-blind fashion to receive either oral enprofylline or theophylline for 5 weeks in addition to their usual maintenance regimens . After a week of placebo xanthine therapy , enprofylline-treated patients received 150 mg of this drug twice daily ( b.i.d . ) for 3 days , 300 mg b.i.d . for 2 weeks , and 450 mg b.i.d . for 2 weeks . Theophylline was administered in identical doses , except that the final dosage increase was not made if plasma theophylline was 12 mg/ml or higher . At 300 mg b.i.d . , both drugs significantly increased morning peak expiratory flow rate ( PEFR ) , the mean increase above baseline being significantly higher for theophylline-treated patients ( 29.9 + /- 37.2 L/min ) than for enprofylline-treated patients ( 17.4 + /- 36.9 L/min ) ( p = 0.023 ) . At 450 mg b.i.d . , improvement in morning PEFR was not significantly different between theophylline-treated ( 31.5 + /- 44.4 L/min ) and enprofylline-treated groups ( 23.5 + /- 48.4 L/min ) . Evening PEFR , FEV1 , and asthma symptom scores also improved significantly , demonstrating no significant difference between groups . The incidence of side effects was also similar between groups . We conclude that both enprofylline and theophylline offer useful bronchodilatation in the maintenance therapy of asthma , enprofylline , 450 mg b.i.d . , being approximately equivalent to theophylline , 300 or 450 mg b.i.d In a double-blind placebo-controlled trial in 24 patients fulfilling the MRC criteria for chronic bronchitis , oral salbutamol 4 mg and slow-release aminophylline ( Phyllocontin ) 450 mg produced similar and significant ( p less than 0.05 ) mean increases in forced expiratory volume in one second ( FEV1 ) . A significantly greater increase in mean FEV1 and forced vital capacity ( FVC ) was seen when both drugs were given although there was no statistical evidence of synergistic interaction . Salbutamol significantly increased the mean distance walked in 12 minutes ( 12MD ) ( p less than 0.02 ) by 56 metres and a similar increase of 54 metres ( p less than 0.001 ) was seen after Phyllocontin . With both drugs in combination mean 12MD increased by 51 metres ( p less than 0.02 cf placebo ) , a change not significantly different from that observed with either drug alone . Oral salbutamol and Phyllocontin improve exercise tolerance in chronic bronchitis . The significantly greater changes in FEV1 and FVC result ing from simultaneous administration of the two drugs are not associated with further improvement in exercise tolerance Dynamic hyperinflation ( DH ) is a major pathophysiologic consequence of airflow limitation during exercise in patients with chronic obstructive pulmonary disease ( COPD ) and an important contributing factor to breathlessness . In this study we aim ed to examine the effect of inhaled beta agonist therapy on DH during exercise in these patients and the relationship between changes in DH and breathlessness . In 13 COPD patients ( mean age 65.1 + /- 2.0 , FEV1 1.20 + /- 0.17 , FEV1/FVC 40 + /- 3 ) we measured pulmonary function tests , exercise breathlessness by Borg score , and exercise flow volume and pressure volume loops on two separate days . Prior to testing , patients r and omly received inhaled placebo or albuterol on the first test day and the alternative medication on the second test day . From measurements of exercise inspiratory capacity ( IC ) , we calculated the end-expiratory and end-inspiratory lung volumes ( EELV , EILV ) . We used esophageal pressure recordings to measure peak inspiratory esophageal pressure ( Pesins ) during exercise and this was related to the maximal capacity for pressure generation taking into account lung volume and airflow changes ( Pcapi ) . Bronchodilator caused significant increase in both FEV1 and FVC ( + 0.23 and + 0.51 , p<0.01 ) . Comparisons of breathlessness , exercise volumes , and pressures were made at the highest equivalent work load . There was a significant reduction in the peak exercise EELV/TLC ( 80 + /- 0.02 % to 76 + /- 0.02 % , p<0.05 ) while the peak EILV/TLC decreased by 2 % ( 97 + /- 1 % to 95 + /- 1 % , p<0.05 ) . The peak Pesins/Pcapi decreased ( 0.79 + /- 0.10 to 0.57 + /- 0.05 , p<0.05 ) , and the Pcapi - Pesins increased ( 7.4 + /- 3 to 13.0 + /- 3 cm H2O , p<0.05 ) . There was significant improvement in neuroventilatory coupling for volume change ( Pesins/Pcapi/VT/TLC 5.45 + /- 0.5 to 3.25 + /- 1.0 , p<0.05 ) . There was a significant reduction in breathlessness as measured by Borg score ( 4.5 + /- 0.7 to 3.1 + /- 0.5 , p<0.05 ) and there was a significant correlation between delta Borg and delta EILV/TLC ( r=0.771 , p<0.01 ) with a trend for Pesins/Pcapi/VT/TLC ( r=0.544 , p=0.067 ) . There was also a significant correlation between delta EELV/TLC and delta Pesins/Pcapi/VT/TLC ( r=0.772 , p<0.01 ) . The relationships between delta Borg , delta resting volumes , and flow rates were not significant . We conclude that in patients with COPD , inhaled bronchodilator reduces exercise DH and improves inspiratory pressure reserve and neuroventilatory coupling . Changes in DH and neuroventilatory coupling were the main determinants of reduced breathlessness BACKGROUND Inhaled glucosteroids and oral theophylline are widely used to treat asthma . We compared the benefits of adding theophylline to inhaled glucosteroid with those of doubling the dose of inhaled glucosteroid in patients with persistent symptoms despite the use of inhaled glucosteroid . METHODS In a double-blind , placebo-controlled trial , we r and omly assigned 62 patients to receive either 400 microg of inhaled budesonide ( low-dose budesonide ) with 250 or 375 mg of theophylline ( depending on body weight ) or 800 microg of inhaled budesonide ( high-dose budesonide ) . All doses were given twice daily for three months . Lung function was measured serially , and patients kept records of peak expiratory flow , symptoms , and albuterol use . The effects of treatment on endogenous cortisol levels were also assessed . RESULTS Both treatments result ed in improvements in lung function that were sustained throughout the study . As compared with treatment with high-dose budesonide , treatment with low-dose budesonide plus theophylline result ed in greater improvements in forced vital capacity ( P=0.03 ) and forced expiratory volume in one second ( P= 0.03 ) . There were significant and similar reductions in beta2-agonist use and the variability of peak expiratory flow , a correlate of bronchial hyperresponsiveness and the severity of asthma . Serum cortisol concentrations were significantly reduced in the group given high-dose budesonide ( from a mean [ + /-SE ] of 18.4+/-2.4 microg per deciliter to 15.9+/-2.1 microg per deciliter , P=0.02 ) but were unchanged in the other group . The median serum theophylline concentration was 8.7 microg per milliliter ( therapeutic range , 10 to 20 ) among those who received theophylline . Both treatments were well tolerated . CONCLUSIONS For patients with moderate asthma and persistent symptoms , low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide produced similar benefits . Effects were achieved at theophylline concentrations below the recommended therapeutic range . The addition of low-dose theophylline to inhaled glucosteroid may be preferable to and cheaper than increasing the dose of inhaled glucosteroid 24 patients with COPD and delta FEV1 greater than 15 % were included in a double-blind crossover study . 7 dropouts due to deterioration of findings and incomplete data reduced the number of assessable patients to 17 . Most of the patients had been pretreated with a slightly higher theophylline dosage before initiation of the study . In the preliminary period a 24-hour profile of the peak flow was set up with a morning and evening theophylline level . During the 5-day treatment intervals a 24-hour profile of the serum theophylline levels and of the peak flow was recorded at two-hour intervals . A complete lung function test was performed in each phase . The pharmacokinetic data of both preparations are comparable . Euphylong showed a bioavailability of 83 % , the maximum of the serum level was attained at night . Serum level variations were only slightly higher than those of the reference drug . Euphylong had a night level of 24 % above the daily average ( reference drug 3 % ) . This was associated in a part of the group , about one-third of the total number of patients , with an improvement of the " morning dip " compared with the preliminary period or the reference drug . Over the entire group of patients there were no differences between both drugs or the preliminary period that could be ascribed to the theophylline premedication . An advantage shown by Euphylong was the better predictability of the serum levels . During the time period of the clinical routine the deviation of the serum level from the actual serum maximum was less than 15 % Background : Chronic continuous airway inflammation caused by eosinophils has been noted to play critical roles in the pathophysiology of bronchial asthma , in addition to reversible obstruction and hypersensitivity of the respiratory tract . Therefore , suppression of chronic airway inflammation has become more important in asthma treatment . Although theophylline has been a conventionally used bronchodilator , it has been recently reported to have concurrent anti-inflammatory effects . Objective : Accordingly , we studied the effects of a slow-release theophylline preparation , Theolong ® , on airway inflammation . Methods : Administration of Theolong 400 mg/day to 24 patients with mild or moderate asthma and measuring eosinophil cationic protein ( ECP ) , a marker of airway inflammation , and eosinophils in sputum and peripheral blood at 4 and 8 weeks . Results : As a result , sputum ECP , serum ECP and sputum eosinophil count ( % ) were significantly lowered after 4 and 8 weeks . Conclusion : Thus , in the theophylline-administered group , slow-release theophylline , Theolong ® , was effective in treating asthma , with anti-inflammatory effects on inflammatory cells besides its bronchodilator action OBJECTIVES To determine whether children with severe acute asthma treated with large doses of inhaled salbutamol , inhaled ipratropium , and intravenous steroids are conferred any further benefits by the addition of aminophylline given intravenously . STUDY DESIGN R and omised , double blind , placebo controlled trial of 163 children admitted to hospital with asthma who were unresponsive to nebulised salbutamol .  RESULTS The placebo and treatment groups of children were similar at baseline . The 48 children in the aminophylline group had a greater improvement in spirometry at six hours and a higher oxygen saturation in the first 30 hours . Five subjects in the placebo group were intubated and ventilated after enrolment compared with none in the aminophylline group . CONCLUSIONS Aminophylline continues to have a place in the management of severe acute asthma in children unresponsive to initial treatment Exercise tolerance in chronic obstructive pulmonary disease ( COPD ) patients treated with oral aminophylline  may be different from those treated with high-dose inhaled ipratropium bromide . The purpose of this study was to compare the effects of therapeutic doses of oral aminophylline with high-dose ipratropium bromide on spirometry and exercise tolerance . The study was conducted on three consecutive days in a double-blind , r and omized , crossover fashion . Baseline studies obtained on each study day included vital signs , simple spirometry and a symptom-limited maximal cardiopulmonary stress test , after which patients received one of the following treatments on each day : Treatment 1 , inhaled ipratropium ( total dose of 144 micrograms ) with placebo tablets ; Treatment 2 , inhaled placebo with oral aminophylline ( 400 mg ) ; Treatment 3 , inhaled placebo and placebo tablets . Simple spirometry was repeated at 60 and 120 min after baseline . Vital signs and cardiopulmonary stress testing was repeated at 120 min . Eighteen patients were enrolled in the study , and 17 of these completed the study . There was a significant ( P < 0.05 ) increase in both forced expiratory volume in 1 s ( FEV1 ) , from 0.75 ( 0.21 ) to 0.92 ( 0.3 ) , and forced vital capacity ( FVC ) , from 1.8 ( 0.79 ) to 2.11 ( 0.84 ) , with high-dose ipratropium despite prior beta-agonist therapy . Lack of improvement in exercise capacity was noted with ipratropium despite improvement in spirometry . These results suggest that elderly patients with severe COPD may have exercise limitation that is not directly dependent on severity of airflow obstruction . Ipratropium bromide and aminophylline demonstrated no acute effects on exercise capacity BACKGROUND Previous clinical therapeutic research has shown that inhaled nedocromil sodium can replace maintenance oral sustained release theophylline in the management of asthma patients . OBJECTIVE To compare directly the efficacy and safety of nedocromil sodium and sustained release theophylline . METHODS Using a r and omized , double-blind , double-dummy , parallel-group design , 105 patients with reversible obstructive airways disease ( 77 asthmatic patients ) recruited from four referred-care clinics received , in addition to their existing therapy , 4 mg nedocromil sodium four times daily or sustained release theophylline ( maximum daily dose 13 mg/kg ) for 6 weeks . Patients with serum theophylline levels within the therapeutic range of 10 to 20 micrograms/mL were retained for efficacy analysis . All were included in a tolerability analysis . Day and nighttime symptoms , inhaled bronchodilator use , morning tightness , cough , and twice daily peak flows were recorded on diary cards . Disease severity , lung function and unusual events were evaluated bi-weekly , and opinion of treatment after 6 weeks . RESULTS Both treatments improved symptoms , inhaled bronchodilator use and lung function to the same extent . Both treatments were very to moderately effective in > 70 % patients . The occurrence of gastrointestinal ( P < .05 ) and central nervous system ( P < .01 ) unusual events was significantly lower for nedocromil sodium compared with theophylline treated patients . CONCLUSIONS Nedocromil sodium and theophylline were equally effective in this group of patients but nedocromil sodium treatment was associated with significantly fewer side effects , and therefore may be the treatment of choice In two groups of patients , 15 with asthma and 15 with chronic bronchitis , the bronchodilator effects of ipratropium bromide , of fenoterol plus theophylline , and of the combination of the three drugs , were compared using a double-blind , single-dose , placebo-controlled format . Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis ( delta FEV1 = .29 L in one hour in asthmatic patients , .18 L in patients with bronchitis ) . In contrast , fenoterol plus theophylline induced a considerably greater effect in asthmatic patients ( delta FEV1 = .41 L in one hour ) than in those with bronchitis ( delta FEV1 = .07 in one hour ) . The use of the three drugs in combination compared with ipratropium bromide alone , or fenoterol plus theophylline alone , result ed in a significant additional bronchodilatation in asthmatic patients . In the patients with bronchitis , the triple combination was clearly superior to fenoterol plus theophylline . A similar trend was present in comparing the triple combination to ipratropium bromide , but the difference did not reach statistical significance . There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive . Asthmatic patients and the physician were able to distinguish the triple combination from placebo . No such ability was demonstrated with respect to those with bronchitis . All three drugs were well tolerated . Side effects were mostly mild , and none was related to the use of ipratropium We tested the hypothesis that the decrease in dyspnea in patients with COPD with inhaled albuterol  is in part due to increased diaphragmatic contractility . Eleven patients with COPD inhaled albuterol or placebo in a double-blind r and omized manner . Subsequently , dyspnea was measured while patients breathed through inspiratory resistors , and diaphragmatic contractility was quantified during maximal inspiratory efforts and after twitch stimulation of the phrenic nerves . Albuterol produced a decrease in dyspnea ( 5 + /- 2 to 4 + /- 2 [ SD ] Borg units , p < 0.01 ) , and increases in maximal transdiaphragmatic pressure ( 92.4 + /- 37.2 to 102.8 + /- 37.2 cm H(2)O , p < 0.03 ) and potentiated twitch transdiaphragmatic pressures ( 21.6 + /- 7.1 to 25.2 + /- 7.6 cm H(2)O , p < 0.02 ) . The decrease in dyspnea correlated with the increases in maximal and twitch transdiaphragmatic pressures : r = -0.64 ( p = 0 . 04 ) and r = -0.65 ( p = 0.04 ) , respectively . Compared with placebo , albuterol produced an increase in inspiratory capacity ( 1.87 + /- 0 . 71 to 2.26 + /- 0.74 L , p = 0.002 ) , which accounted for the increases in maximal and twitch transdiaphragmatic pressures . The decrease in dyspnea correlated with the increase in inspiratory capacity ( r = -0 . 62 , p = 0.04 ) , but not with the increase in FEV(1 ) ( r = -0.13 , p = 0 . 72 ) . In conclusion , albuterol relieves dyspnea and enhances respiratory muscle output in patients with COPD primarily by improving the length-tension relationship of the diaphragm rather than by improving its contractility To investigate the effect of theophylline on  sleep and sleep-disordered breathing in patients with chronic obstructive pulmonary disease ( COPD ) , we studied 12 male nonhypercapnic subjects with a mean + /- SEM age of 62.8 + /- 2.5 yr and a FEV1 of 1.36 + /- 0.11 L using a r and omized double-blind crossover protocol . Sustained-action theophylline ( 250 mg three times or four times a day ) or placebo was administered for 2 days , and the alternate drug was administered on the following 2 days . Sleep studies were performed on Nights 2 and 4 with spirometry at 9:00P.M. and 7:00A.M. Two puffs of metaproterenol or albuterol were administered at 10:00P.M. on both study nights . A theophylline level , drawn at bedtime ( 10:00 to 11:00P.M. ) , was 14.2 + /- 0.78 micrograms/ml on the theophylline nights and less than 2 on placebo nights . The morning FEV1 was significantly better during theophylline administration ( 1.27 + /- 0.12 versus 1.00 + /- 0.11 L , p less than 0.001 ) . The mean arterial oxygen saturation ( SaO2 ) and transcutaneous carbon dioxide pressure ( PCO2 ) were also better during NREM sleep on theophylline nights . Neither the mean SaO2 and transcutaneous PCO2 during REM sleep nor the apnea plus hypopnea index ( events per hour of sleep ) differed between placebo and theophylline nights . Theophylline administration did not impair the amount or architecture of sleep as neither total sleep time nor the fraction of time spent in Stages 1 , 2 , and 3/4 and REM differed between the two regimens . The number of arousals per hour of sleep was slightly less on theophylline nights ( 19.9 + /- 1.7 versus 24.9 + /- 2.7 , p less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The effect of theophylline on sleep quality and cognitive performance in patients with obstructive lung disease has been the subject of controversy . To examine the direct effects of theophylline on sleep quality and cognitive performance , without confounding effects from bronchodilatation , we have undertaken a study of the drug in healthy subjects . A double-blind , placebo-controlled crossover protocol was used to study the effect of oral sustained-release theophylline ( Theodur ) on subjective sleep quality , objective sleep quality , and cognitive performance . Overnight sleep studies  were carried out on Nights 13 and 14 of each 2-wk study limb , and cognitive performance tests administered on Days 1 and 13 of each limb . A total of 18 subjects satisfactorily completed the study ( 8 males , median age 37 , range 24 to 67 yr ) .  Theophylline levels were median 10.2 , range 2.3 to 13.3 micrograms/ml on Day 1 and 14.7 , range 9.6 to 17.5 micrograms/ml on Day 13 . No significant difference was observed between theophylline and placebo on subjective or objective sleep quality or on acute or medium-term cognitive performance . We conclude that theophylline does not affect sleep quality or cognitive performance in normal adults A multicentre , double-blind , r and omized trial was carried out in 11 Italian Pneumologic Clinics to investigate the therapeutic efficacy and tolerability of doxofylline compared with slow-release theophylline in 139 patients ( 86 males , 53 females ) aged 17 - 77 years suffering from reversible chronic airways obstruction . The two groups of 69 patients on doxofylline and 70 patients on theophylline did not differ in their baseline clinical and functional parameters . After one week of wash-out , the two drugs were administered orally at a dose of 400 mg twice daily of doxofylline and 300 mg twice daily of theophylline . The treatment and follow-up lasted 28 days . Inhaled salbutamol  on dem and was allowed in the wash-out week and throughout the trial . The average serum levels at day 14 and 28 were : doxofylline 7.5 and 8.5 micrograms/ml ; theophylline 10.4 and 7.95 micrograms/ml respectively . Both drugs significantly increased spirometric parameters ( p less than 0.001 for all tests ) and significantly reduced salbutamol consumption ( p less than 0.001 for both drugs ) . Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects :  ( doxofylline 12 ; theophylline 37 ) or number of drop-outs due to side-effects  ( doxofylline 5 ; theophylline 10 ) . From these results doxofylline seemed to be a good alternative to theophylline in the treatment of reversible chronic airway obstruction in view of its better safety profile To determine the effect of theophylline on respiratory muscle efficiency ( RME ) , 12 normal subjects were given theophylline vs placebo in a double-blind , r and omized crossover protocol . Spirometry , resting energy expenditure , minute ventilation , RME and oxygen cost of breathing were measured at baseline , after taking theophylline , and after placebo . RME was calculated by dividing the added work required to breathe through a threshold load by the added energy consumed during loaded breathing . Oxygen cost of breathing was calculated by dividing the increase in oxygen consumption induced by breathing an air/carbon dioxide mixture by the associated increase in minute ventilation . RME increased from 3.3 + /- 1.6 % at baseline to 7.9 + /- 3.2 % after theophylline ( p < 0.01 ) but did not change significantly after placebo ( 4.8 + /- 2.4 % ) . Oxygen cost of breathing decreased from 3.9 + /- 2.4 mL O2 per liter at baseline to 1.7 + /- 0.7 mL O2 per liter after theophylline ( p < 0.05 ) but did not change significantly after placebo ( 2.8 + /- 1.3 mL O2 per liter ) . Theophylline use was also associated with an 18 % increase in minute ventilation ( p < 0.01 ) and a 15.7 % increase in resting energy expenditure ( p < 0.01 ) . Theophylline improves measured RME and reduces oxygen cost of breathing in normal subjects . These effects are offset by increases in resting energy expenditure and minute ventilation BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) tend to develop secondary erythrocytosis to compensate for their chronic hypoxia . Theophylline has recently been shown to reduce hematocrit and erythropoietin blood levels in normal subjects and in patients with erythrocytosis after renal transplantation . OBJECTIVE To determine whether theophylline may be used to lower the hematocrit in patients with COPD . METHODS Two hundred four patients with COPD were studied retrospectively and 10 patients prospect ively ( 8 starting treatment with the drug [ group 1 ] and 2 who suspended its long-term use [ group 2 ] ) for the correlation between theophylline therapy and hematocrit and erythropoietin level . RESULTS In the patients studied retrospectively , lower hematocrits were found in the theophylline-treated than in the untreated patients ( 0.43 + /- 0.006 vs 0.46 + /- 0.007 , respectively ; P < .002 ) . Twelve untreated patients and 2 of those treated with theophylline had hematocrits above 52 % . Oxygen saturation levels were similar in both groups , and exclusion of patients with oxygen saturation lower than 88 % did not change the pattern , suggesting that the effect of theophylline could not be entirely explained by improved oxygen availability . Seven of the 8 patients studied prospect ively in group 1 ( P < .02 ) and the 2 patients in group 2 showed inverse correlations between hematocrits and theophylline administration . A similar pattern was observed with serum erythropoietin levels in 5 of 7 patients studied . The effects were reproducible on rechallenge in 3 of the 4 patients in group 1 and the 2 patients in group 2 . CONCLUSIONS Theophylline may have a beneficial effect in treatment and prevention of erythrocytosis in patients with COPD We studied the effects of theophylline on diaphragmatic strength and fatigue in 15 patients with severe chronic obstructive pulmonary disease . Diaphragmatic strength was assessed by measurement of the transdiaphragmatic pressure generated at functional residual capacity during a maximal inspiratory effort against closed airways . Diaphragmatic fatigue was induced by resistive loaded breathing . The electrical activity of the diaphragm was recorded with an esophageal electrode during the fatigue runs , and the high-low ratio of the electrical signal was analyzed to assess diaphragmatic fatigue . Studies were performed before and after 7 and 30 days of theophylline administration ( mean plasma level , 13 + /- 2 mg per liter ) . A control group received a placebo instead of theophylline . Theophylline increased maximal transdiaphragmatic pressure by 16 per cent after 7 days of administration ( P less than 0.01 ) , and this increase persisted after 30 days . No significant change in maximal transdiaphragmatic pressure was observed in the group given the placebo . Theophylline also suppressed diaphragmatic fatigue in all patients who received it . We conclude that theophylline has a potent and long-lasting effect on diaphragmatic strength and fatigue in patients with fixed airway obstruction Although orally administered theophylline has been prescribed widely in patients with nonreversible airway obstruction , symptomatic benefit has not been established . To assess the effects of orally administered theophylline on dyspnea , we performed a r and omized , double-bind , crossover , placebo-theophylline clinical trial in 12 ambulatory male patients with moderate to severe nonreversible airway obstruction . Dyspnea was rated using 2 clinical indexes based on 3 components affecting breathlessness : functional impairment , magnitude of task that evokes dyspnea , and the associated magnitude of effort . Dyspnea and physiologic parameters were measured on 4 occasions : at baseline , 4 wk after initial treatment , a second baseline after a 2-wk washout period , and 4 wk after the second medication . For the 12 patients , mean age ( + /- SD ) was 60 + /- 7 yr , forced expiratory volume in one second was 1.36 + /- 0.67 L ( mean , 40 % of predicted ) , and arterial oxygen tension was 71 + /- 10 mmHg . During the treatment phase , all patients had a therapeutic theophylline blood level ( range , 12 to 19 micrograms/ml ) . Theophylline significantly decreased the components of functional impairment ( p = 0.02 ) and magnitude of task ( p = 0.02 ) relating to dyspnea , as well as the overall dyspnea rating ( p = 0.01 ) . There were no significant differences between placebo and theophylline therapy for spirometry , arterial blood gas tensions , and the 12-min walking distance . Thus , sustained-release theophylline significantly reduced dyspnea in these ambulatory patients with moderate to severe nonreversible airway obstruction without altering lung function , gas exchange , or exercise performance Orally administered theophylline is commonly prescribed for patients with chronic obstructive pulmonary disease ( COPD ) . It would be advantageous to predict those patients who will or will not respond to this methylxanthine . Forty men with COPD received placebo and theophylline orally , each for 1 month in a double-blind , single cross-over fashion . The acute response of the forced expiratory volume in one second ( FEV1 ) to isoproterenol inhalation ( 015 mg ) during placebo therapy was determined . The subjective and objective responses after 1 month of therapeutic theophylline concentrations ( 15.1 + /- 4.2 microgram/ml ) , mean + /- SD ) in these clinical ly stable subjects also were measured . The sensitivity and specificity of isoproterenol aerosolization for predicting an objective response to theophylline was 75 and 96 % , respectively . We conclude that isoproterenol inhalation can predict the response to orally administered theophylline in patients with COPD We compared the frequency and severity of cardiac arrhythmias during combined oral theophylline and inhaled salbutamol vs. salbutamol therapy alone in 18 patients with moderate to severe chronic obstructive pulmonary disease who had concurrent cardiac disease . Seventeen patients showed at least one supraventricular premature complex ( SVPC ) on the 24-h ECG recording when receiving salbutamol alone : eight patients had isolated SVPCs , less than 10/h ; five patients had greater than or equal to 10 SVPCs/h ; eight patients showed runs of supraventricular tachycardia or paroxysmal atrial fibrillation . Seventeen patients also had at least one ventricular premature complex : seven patients had less than 10 isolated PVCs/h , five patients greater than or equal to 10 PVCs/h ; eight patients had paired or multifocal PVCs and one patient a run of ventricular tachycardia . The addition of oral theophylline at an average dose of 600 mg in the evening ( blood concentrations showed a mean maximum of 13.4 + /- 4.0 ( SD ) and minimum of 5.5 + /- 2.9 mg/l ) had no influence on the frequency or severity of either ventricular or supraventricular arrhythmias . Thus , cardiac arrhythmias are very common in patients with chronic obstructive pulmonary disease and concomitant heart disease , but oral theophylline added to a regimen of salbutamol does not seem to affect the occurrence or severity of arrhythmias Theophylline is known to alter sleep architecture because of its affinity to adenosine receptors . One of the consequences of disrupted sleep is impaired cognitive performance . A single-blind , r and omized cross-over study of eight male chronic obstructive pulmonary disease ( COPD ) patients was undertaken to evaluate the effects of theophylline versus doxofylline on sleep architecture .  The patients , who were all ex-smokers , had been treated with theophylline . Mean age was 53 + /- 12 yrs , forced expiratory volume in one second ( FEV1 ) 50 + /- 22 % predicted and forced vital capacity ( FVC ) 70 + /- 18 % predicted . Following a wash-out period , four patients were given oral slow-release theophylline ( T ) ( 300 mg b.i.d . ) for one week , followed by a cross-over to doxofylline ( D ) ( 400 mg t.i.d . ) for a second week . The other four patients were given the drugs in the reverse order . All patients underwent polysomnography at baseline and at the end of each week of treatment . The number of arousals per hour was 5.5 + /- 2.9 at baseline , 9.4 + /- 5.2 during T treatment and 5.4 + /- 4.4 during D treatment . During T treatment , sleep efficiency was 60 + /- 19 % vs 75 + /- 13 % recorded at baseline trial and 68 + /- 25 recorded during D treatment . Sleep quality , during T treatment , was poorer than at baseline , with a greater increase in the percentage of wakefulness and more stage 2 sleep than at baseline . Slow wave sleep was reduced with both treatments , particularly D. Neither drug affected the arterial oxygen saturation ( Sao2 ) or respiratory rate during sleep . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND The effects of theophylline or anticholinergic agents on exercise capacity in patients with chronic obstructive pulmonary disease ( COPD ) remain controversial . The aim of the present study was to compare the effect of an oral theophylline with an inhaled anticholinergic agent and to examine the effects of combined therapy on exercise performance using progressive cycle ergometry . METHODS Twenty one men with stable COPD and a mean ( SD ) forced expiratory volume in one second ( FEV1 ) of 1.00 ( 0.40 ) l were studied .  Theophylline ( 600 or 800 mg daily ) , ipratropium bromide ( 160 μg ) , a combination of both drugs , and placebo were given in a r and omised , double blind , four period crossover design study . Spirometric data , pulse rate , and blood pressure were assessed before and at 90 and 120 minutes after inhalation . Symptom limited progressive cycle ergometer exercise tests ( 20 watts/min ) were performed 90 minutes after each inhalation , and dyspnoea was measured during exercise using the Borg scale . RESULTS The mean ( SD ) serum theophylline concentration was 18.3 ( 6.3 ) μg/ml , and seven patients had side effects during treatment with theophylline . Theophylline and ipratropium bromide produced greater increases in FEV1 , maximal oxygen consumption , maximal minute ventilation , and several dyspnoea ratios than placebo . There were no differences between theophylline and ipratropium bromide except in maximal heart rate . A combination of both drugs produced greater improvements in pulmonary function and exercise capacity than either drug alone . CONCLUSIONS Both high dose theophylline and high dose ipratropium bromide  improved exercise capacity in patients with stable COPD . Although data based on short term effects can not be directly applied to long term therapy , theophylline added to an inhaled anticholinergic agent may have beneficial effects on exercise capacity in patients with COPD A 1-yr multicentre two-tailed r and omized open study was conducted in 15 centres in Italy , with the aim of comparing the clinical efficacy ( over 3 months ) and tolerability ( over 1 yr ) of salmeterol with those of oral theophylline in patients with reversible chronic obstructive pulmonary disease ( COPD ) . Patients with reversible COPD ( forced expiratory volume in one second ( FEV1 ) 50 - 80 % , FEV1 after bronchodilator > 12 % , n = 138 ) were r and omized to receive salmeterol powder ( 50 micrograms b.i.d . with Diskhaler , n = 66 ) or individually dose-titrated slow-release oral theophylline capsules so as to obtain a serum concentration of theophylline ranging 10 - 20 micrograms.mL-1 ( n = 72 ) . During the 2-week run-in period , nonadmitted medications were discontinued and patients had to present with respiratory symptoms on at least four of the last seven days . Following r and omization , patients were required to monitor daytime and night-time symptoms , additional use of as-required salbutamol , and morning and evening peak expiratory flow ( PEF ) for 3 months . Spirometric measurements and assessment of the quality of life were performed every 3 months for 1 yr . Salmeterol was proven to be statistically more effective than theophylline in : 1 ) increasing the maximum value of morning PEF ; 2 ) increasing the percentages of days and nights without symptoms ; 3 ) reducing the need for additional salbutamol during daytime and night-time ; and 4 ) increasing quality of life in terms of physical and social activities , mental health and psychophysical energy , assessed 3 months after the beginning of treatment . Salmeterol was no more effective than theophylline in increasing : 1 ) forced vital capacity and FEV1 at the various measurements ; 2 ) maximum evening PEF value ; and 3 ) quality of life after the first 3 months of treatment . Neither treatment induced significant side-effects over the 1-yr treatment . This study confirms that inhaled salmeterol is more effective than oral theophylline in long term treatment of reversible obstructive pulmonary disease To investigate the efficacy of bronchodilators in patients with irreversible chronic obstructive pulmonary disease ( COPD ) , we conducted a double-blind , r and omized , four-phase , crossover comparison between placebo , oral theophylline , inhaled salbutamol , and a combination of both drugs in 12 patients with stable COPD ( mean age , 63 years ) whose increase in forced expiratory volume in 1 s ( FEV1 ) was less than or equal to 15 percent following 200 micrograms of inhaled salbutamol .  Patients received two weeks of therapy with each of the test regimens . Both theophylline and salbutamol result ed in statistically significant improvement in FEV1 , forced vital capacity ( FVC ) , slow vital capacity ( SVC ) , residual volume ( RV ) , airway resistance ( Raw ) , and maximum expiratory flow rate at 50 percent of vital capacity ( V50 ) . In most instances , there were no significant differences between theophylline and salbutamol . Combination therapy produced significantly greater improvement in FEV1 , FVC , V50 , Raw , and RV than either agent alone . The two drugs interacted in an additive fashion . Neither of the drugs , used singly , significantly reduced the severity or incidence of symptoms . The reduction in dyspnea and wheeze during combination therapy approached statistical significance ( p = 0.06 ) and patient preference was significantly in favor of the combination regimen . None of the active treatments produced significantly more side effects than placebo . We conclude that theophylline and inhaled salbutamol produce significant , and approximately equal , improvement in pulmonary function in patients traditionally classified as suffering from " irreversible " COPD . The combination of theophylline and inhaled salbutamol generally results in additional improvement over that obtained with either drug used alone and this improvement is reflected by reduced symptomatology and treatment preference At rest and during exercise , noninvasive studies of cardiopulmonary physiology in patients with chronic obstructive pulmonary disease ( COPD ) were carried out to determine the objective benefits of commonly used oral bronchodilator drugs in 15 stable patients without cardiovascular disease or reversible obstruction of airflow .  Theophylline , terbutaline , a combination of theophylline and terbutaline , and placebo were given for ten days each in a r and omly sequenced double-blind protocol for out patients . Spirometric values , the ratio of physiologic dead space to tidal volume ( VDp/VT ) , and the alveolar-arterial oxygen pressure difference ( P[A-a]O2 ) were studied at rest on each regimen . During steady-state exercise the changes in VDp/VT and P(A-a)O2 , as well as the ventilatory equivalent for oxygen and oxygen pulse , were measured . When compared with placebo , no significant change was noted in the previously mentioned measurements with any regimen , with the exception of a small improvement in the forced expiratory volume in one second , which was significant for all regimens . These findings suggest that commonly used oral bronchodilator drugs in usual doses may have small effects on airflow even in " irreversible " COPD but that the objective effect of these agents on gas exchange during rest and exercise is not significant We wished to determine which resting spirometric parameters best reflect improvements in exercise tolerance and exertional dyspnea in response to acute high-dose anticholinergic therapy in advanced COPD . We studied 29 patients with stable COPD ( FEV(1 ) = 40 + /- 2 % predicted [ % pred ] ; mean + /- SEM ) and moderate to severe chronic dyspnea . In a double-blind placebo-controlled cross-over study , patients performed spirometry and symptom-limited constant-load cycle exercise before and 1 h after receiving 500 micrograms of nebulized ipratropium bromide ( IB ) or saline placebo . There were no significant changes in spirometry , exercise endurance , or exertional dyspnea after receiving placebo . In response to IB ( n = 58 ) : FEV(1 ) , FVC , and inspiratory capacity ( IC ) increased by 7 + /- 1%pred , 10 + /- 1%pred , and 14 + /- 2%pred , respectively ( p < 0.001 ) , with no change in the FEV(1)/FVC ratio . After receiving IB , exercise endurance time ( Tlim ) increased by 32 + /- 9 % ( p < 0.001 ) and slopes of Borg dyspnea ratings over time decreased by 11 + /- 6 % ( p < 0.05 ) . Percent change ( % Delta ) in Tlim correlated best with DeltaIC%pred ( p = 0.020 ) and change in inspiratory reserve volume ( DeltaTLC%pred ) ( p = 0.014 ) , but not with DeltaFVC%pred , DeltaPEFR%pred , or DeltaFEV(1)%pred . Change in Borg dyspnea ratings at isotime near end exercise also correlated with DeltaIC%pred ( p = 0.04 ) , but not with any other resting parameter . Changes in spirometric measurements are generally poor predictors of clinical improvement in response to bronchodilators in COPD . Of the available parameters , increased IC , which is an index of reduced resting lung hyperinflation , best reflected the improvements in exercise endurance and dyspnea after IB . IC should be used in conjunction with FEV(1 ) when evaluating therapeutic responses in COPD The traditional role of theophylline as a bronchodilator has been exp and ed by recent findings that suggest this drug has more than smooth muscle relaxant properties . Several investigators indicate that theophylline has an inotropic effect on respiratory muscle , causing enhanced muscular contraction and prevention of muscle fatigue . In animal studies , the drug enhanced respiratory muscle contraction by 15 - 20 % , with levels in the upper end of the therapeutic range ( 15 - 20 mg/L ) . Results of studies in healthy volunteers and patients with lung disease , however , are conflicting . Five clinical trials demonstrated increased diaphragmatic contractility , whereas seven trials showed no effect , with five referring to the diaphragm and the remaining two to the sternomastoid muscle . Disparity in outcomes may be attributed to differences in patient population s , study design s , and techniques used to determine diaphragmatic contractility . Few long-term trials exist that document significant clinical benefit . Theophylline may prove to be of value in selected population s , such as adults with hypercapnic obstructive lung disease AIM To investigate whether low dose theophylline has an anti-inflammatory effect in asthma . METHODS Nineteen asthmatic subjects were given 200 mg sustained-release theophylline preparation twice daily for 4 weeks . The mean serum concentration of theophylline was 7.9 mg/L. The percentage of eosinophils , EG2 + eosinophils , and the level of eosinophil cationic protein ( ECP ) in sputum pre- and post-administration were detected by Wright 's stain , immunocytochemistry , and immuno-CAP system , and the symptom scores and lung function were evaluated as well . The above indices for 10 healthy subjects were regarded as control . RESULTS Before using theophylline , sputum eosinophils , EG2 + eosinophils , and ECP in asthmatic group were much higher than those of healthy group . After four weeks administration , there were great decreases in percentage of total eosinophils ( 40 % + /- 17 % vs 29 % + /- 11 % , P < 0.01 ) , activated ( EG2 + ) eosinophils ( 28 % + /- 9 % vs 10 % + /- 8 % , P < 0.01 ) and in the concentration of sputum ECP [ ( 373 + /- 206 ) vs ( 220 + /- 132 ) microg/L , P < 0.01 ] . The symptom scores decreased greatly ( 7.1 + /- 1.2 vs 5.4 + /- 1.6 , P < 0.01 ) . There was a marked increased in forced expiratory volume one second ( FEV(1.0 ) ) after administration ( 2.2 + /- 0.6 vs 2.4 + /- 0.5 , P < 0.01 ) . The FEV(1.0 ) % of asthmatic subjects after administration increased ( 60 % + /- 13 % vs 65 % + /- 13 % , P < 0.01 ) , too . CONCLUSION These results indicated that low dose theophylline had inhibitory action on airway inflammation in asthma with noticeable improvement of the patients ' symptoms and lung function Circadian alterations in lung function occur in respiratory disorders , with the nadir during the sleep-related hours . Higher therapeutic serum theophylline concentrations ( STC ) during the night have been shown to improve lung function in reversible airway disease . To determine what effect higher nocturnal STC would have in patients with chronic obstructive pulmonary disease ( COPD ) on overnight lung function , oxygen saturation , and sleep quality , two different theophylline products were used to give higher or lower STC during the night . We found that with a higher STC ( 15.0 + /- 1.0 versus 11.0 + /- 1.0 micrograms/ml , p = 0.005 ) at 7:00 A.M. , the overnight changes in FEV1 ( + 7.4 + /- 5.7 % versus -18.9 + /- 7.9 % , respectively ) and FVC ( + 1.8 + /- 7.5 % versus -17.2 + /- 3.9 % , respectively ) were significantly better . However , there was no apparent effect on oxygen saturation ( mean sleep values for higher STC were 85.3 + /- 1.2 % , and for lower STC they were 86.5 + /- 0.8 % ) . The higher STC did not adversely affect sleep latency , sleep efficiency , or sleep staging . We conclude that a higher therapeutic STC during sleep will improve lung function without altering oxygen saturation in patients with COPD . In this group of patients , the higher STC did not interfere with sleep characteristics Because it is common to perform a bronchodilator challenge while a patient continues oral methylxanthines , we wanted to determine if this procedure might be misleading for subsequent therapy . Thirty-eight men with a long smoking history and a clinical diagnosis of chronic obstructive pulmonary disease ( COPD ) were given placebo and oral theophylline ( each for one month ) in a double-blind , single-crossover manner . Pulmonary functional tests were performed before and after isoproterenol nebulization on the final day of each 4-wk period . There were significantly larger increases in FVC ( p less than 0.001 ) and FEV1 ( p less than 0.01 ) after isoproterenol challenge when receiving placebo than when receiving theophylline . According to the intermountain Area rating criteria , only the results after isoproterenol challenge during placebo therapy would indicate improvement . These results suggested that isoproterenol inhalation challenge be performed after methylxanthines have been discontinued if used to predict which patients with COPD may respond to oral theophylline therapy Doxophylline , or 2-(7'-theophyllinemethyl)1,3-dioxolane , is a theophylline derivative which has shown interesting bronchodilating activity , and it appears to determine few adverse effects . The aim of the present investigation was to evaluate clinical therapeutic effects of the drug in the treatment of 2 groups of patients suffering from moderate to severe chronic obstructive pulmonary disease differing in acute response to the inhaled beta 2-agonist salbutamol  and to compare changes of lung function tests to serum concentration of doxophylline . We studied 67 patients with chronic obstructive pulmonary disease ( median age 63 years , 9 females and 58 males ) who were all clinical ly stable at the time of the study . Patients were separated into 2 groups on the basis of their reaction to inhalation of 200 micrograms of salbutamol : those with an increased FEV1 of more than 20 % from baseline value ( group 1 ) , and those with no increase ( group 2 ) . Doxophylline was administered orally at the dose of 400 mg 3 times daily . Serum levels of doxophylline were determined by high-pressure liquid chromatography . Spirometry and blood gas analysis were performed before and 10 days after treatment . Four patients stopped drug assumption because of side effects ( 3 for dyspepsia and 1 for anxiety ) . In group 1 ( 34 patients ) , a significant increase in SVC , FVC , FEV1 , FEF 25 - 75 % and PEFR was observed . In group 1 ( 29 patients ) , only PEFR significantly increased . No modifications in blood gas analysis were observed . The mean serum level of doxophylline  was 14 micrograms/ml in group 1 and 9 micrograms/ml in group 2 : the difference was statistically significant . The relation between serum levels of doxophylline and FVC showed an increase in the parameter up to the concentration of 12 - 13 micrograms/ml , after which a plateau phase was observed . On the basis of our data , doxophylline appears to have an interesting bronchodilating effect in patients responsive to the inhaled beta 2-agonist salbutamol . The lower limit of the therapeutic range seems to be 12 - 13 micrograms/ml . The upper limit of the therapeutic range was not determined because it was not possible to obtain serum sample s when side effects occurred The efficacy of bronchodilator therapy was assessed in the long-term management of patients with chronic bronchitis and varying degrees of reversible air-flow obstruction . Twenty-five patients with a mean forced expiratory volume in one second ( FEV1 ) 38.7 % predicted received : optimized doses of orally administered , sustained-release theophylline , inhaled salbutamol ( 200 micrograms 4 times a day ) , a combination of the 2 drugs , and identical placebo therapy for periods of 3 wk in a r and omized , double-blind , crossover trial . Patients who deteriorated during treatment were assessed immediately and design ated " treatment failures " if additional therapy proved necessary . Such " failures " occurred in 9 patients with placebo , in 8 with salbutamol , in 6 with theophylline , and in only 1 with combined therapy . Using a ranking system based on " treatment failures " and mean daily peak flow rates , first preference was given to combined therapy in 13 patients , theophylline in 6 , salbutamol in 4 , and placebo in 2 . Thus , both combined therapy ( p less than 0.001 ) and theophylline ( p less than 0.05 ) were better than placebo , but this was not so for inhaled salbutamol . Objective improvements in FEV1 and forced vital capacity were a consistent finding with combined therapy compared with placebo , although not with single agents , and additive effects were clearly demonstrated . In the subgroup of patients able to tolerate placebo therapy , no subjective benefit could be discerned during any of the 3 periods of active treatment . Thus , the combination of orally administered , sustained-release theophylline and inhaled salbutamol offered significant advantages in the clinical control of patients with chronic bronchitis with air-flow obstruction A crossover pilot study was undertaken to compare the acceptability of controlled release salbutamol tablets ( 8 mg twice daily ) with a sustained release theophylline preparation ( 400–800 mg given once each night ) in patients with reversible obstructive airways disease . A 2-week run-in period was used to titrate the theophylline dosage . Patients were then allocated at r and om to one of the treatments before being immediately crossed over to the other for a further 4 weeks . Thirty-two patients , aged 17–66 years , entered the trial . Seventeen patients ( 53 % ) were withdrawn . The majority of the 13 withdrawals due to side-effects of theophylline occurred during the run-in period . There were no statistically significant differences between treatments for either lung function tests performed at the clinic or for peak expiratory flow rate recorded by the patients . The non-asthma symptom score was significantly higher with theophylline than with the salbutamol preparation .  A preference for treatment with the controlled release salbutamol tablets  was expressed by 11/15 patients The effects of theophylline on pulmonary function and gas exchange during rest , sleep , and exercise were assessed in 10 patients with severe but stable chronic obstructive pulmonary disease ( COPD ; median FEV1 , 31 % of predicted ) . The study was r and omized , double blind , placebo controlled , and crossover in design , with each study period lasting 3 wk , and all other usual bronchodilator therapy was continued unchanged . All patients had detailed pulmonary function tests , in addition to exercise testing and overnight sleep studies by st and ard polysomnography . Theophylline significantly improved gas exchange during rest , exercise , and sleep . Awake resting arterial blood gases showed a higher PaO2 on theophylline ( 78 [ 53 to 93 ] mm Hg , median [ range ] ) than placebo ( 72 [ 47 to 83 ] mm Hg ; p < 0.01 by ANOVA ) , and PaCO2 was lower on theophylline ( 42 [ 38 to 54 ] ) compared with placebo ( 45 [ 40 to 51 ] , p < 0.05 by ANOVA ) . Arterial oxygen saturation ( SaO2 ) was significantly higher on theophylline than placebo during exercise and sleep ( p < 0.01 ) , and transcutaneous CO2 was lower during sleep ( p < 0.05 ) . Theophylline also result ed in significantly improved pulmonary function and reduced trapped gas volume ( p < 0.05 ) . Exercise performance was no different during theophylline or placebo phases of the study . Sleep quality , however , was significantly impaired on theophylline . We conclude that theophylline has clinical ly significant benefits in patients with severe COPD 131 asthmatics aged 12 - 65 years , who still had symptoms despite inhaled or oral bronchodilators , were included in this double-blind group comparative study involving nedocromil sodium ( 2 puffs of 2 mg each twice daily ) and placebo ( 2 puffs twice daily ) . The study was carried out at 8 centers over six weeks . Under nedocromil sodium , cough , dyspnea and severity of attacks were reduced significantly . Overall patient assessment also clearly favoured the active substance . Nedocromil sodium was also superior to placebo in terms of the improvement of lung function ( FEV1 , FVC and PEFR ) .  26 patients complained of unusual symptoms ( 12 under nedocromil sodium , 14 under placebo ) .  Nedocromil sodium proved to be an effective , safe and well-tolerated drug in the antiinflammatory long-term treatment of reversible obstructive airways disease To assess the effects of theophylline in chronic obstructive pulmonary disease , we conducted a r and omized , placebo-controlled , double-blind , crossover trial in 60 patients with severe but stable disease . The patients ( mean age , 61 years ) were studied before and after two months of placebo and two months of treatment with a sustained-release preparation of theophylline ( 10 mg per kilogram of body weight per day ) , administered orally . The two treatments were administered in a r and om order and separated by an eight-day washout period . After taking theophylline for two months ( mean plasma concentration , 14.8 mg per liter ) , as compared with the two months of placebo , the patients had significant improvements in dyspnea , pulmonary gas exchange ( partial pressure of arterial oxygen , 66 vs. 61 mm Hg [ P less than 0.0001 ] ; partial pressure of arterial carbon dioxide , 44 vs. 49 mm Hg [ P less than 0.0001 ] ) , vital capacity ( 63 percent vs. 58 percent of the predicted value [ P less than 0.0001 ] ) , and forced expiratory volume in one second ( 36 percent vs. 32 percent of the predicted value [ P less than 0.0001 ] ) , with no significant change in airway resistance or functional residual capacity . Minute ventilation increased by a mean of 18 percent ( P less than 0.0001 ) in the patients taking theophylline because of increased tidal volume , with no change in respiratory frequency . The respiratory-muscle performance of the patients taking theophylline improved by approximately 29 percent ( P less than 0.0001 ) , as indicated by a decline in the ratio of inspiratory pleural pressure during quiet breathing to maximal pleural pressure . We conclude that theophylline improves respiratory function and dyspnea in patients with severe chronic obstructive pulmonary disease and that these improvements are probably due to better respiratory-muscle performance Therapeutic response to theophylline in asthma is generally attributed to its effect in increasing intracellular 3',5 ' cyclic adenosine monophosphate ( cAMP ) by competitive inhibition of cAMP phosphodiesterase . However , because of discrepancies between therapeutic serum theophylline concentration achieved clinical ly and those required for in vitro phosphodiesterase inhibition , we explored the possibility that theophylline may act through adrenomedullary secretion of catecholamines . Five healthy , nonasthmatic male and female adults were studied with a double-blind , r and omized , crossover protocol . Theophylline ( 5 mg/kg ) and placebo were administered in a capsule dosage form . Plasma catecholamines epinephrine ( E ) , norepinephrine ( NE ) , and dopamine ( DA ) were measured by a radioenzymatic assay at baseline and after administration of theophylline at 1 , 2 , and 3 hr . Significant differences between theophylline- and placebo-treated groups ( p less than 0.05 ) were seen at 3 hr for mean percentage increase over baseline with E ( 120 % + /- 25.3 % ) and NE ( 48.02 % + /- 17.94 % ) after theophylline therapy ( mean peak level 7.2 + /- 0.48 micrograms/ml ) . Epinephrine plasma concentration was significantly greater ( p less than 0.001 ) at 3 hr compared with baseline ( 105 + /- 16 vs 56 + /- 18 pg/ml ) , while NE ( 448 + /- 52 vs 320 + /- 36 pg/ml ) did not attain significance ( p = 0.136 ) . A significant correlation ( p less than 0.05 ) was found between the percentage increase over basal for E ( r = 0.58 ) and NE ( r = 0.66 ) and serum theophylline levels . DA was not significantly increased at any time period . Thus theophylline in clinical ly relevant concentration appears to stimulate adrenomedullary secretion of catecholamine . Whether this is an important mechanism of action in asthma or explains some side effects of theophylline remains to be determined Enprofylline is a potent bronchodilating xanthine derivative that has been shown to have little or no ability to antagonize adenosine in a variety of cell types . In eight patients with chronic obstructive lung disease , a single dose of enprofylline ( 3.5 mg/kg ) was given orally . A double blind , r and omized , crossover comparison was made with oral theophylline ( 9.5 mg/kg ) which is a potent and general adenosine receptor antagonist .  Forced expiratory volume ( FEV1 ) , vital capacity , tremor of h and s , heart rate , and blood pressure were followed for 6 h. Plasma concentrations of both drugs were monitored . At doses producing significant bronchodilation , theophylline caused a significant increase in tremor of h and s whereas enprofylline did not . There were no significant changes in heart rate or blood pressure after either drug . It is suggested that the lack of tremorogenic effect of enprofylline is related to its lack of CNS-stimulating behavioural effects and , hence , may reflect its low tendency to antagonize neuro-depressant actions of adenosine . The adenosine-blocking mechanism may not be important for the bronchodilating effects of xanthines The bronchodilator effects of a single dose of ipratropium bromide aerosol ( 36 micrograms ) and short-acting theophylline tablets ( dose titrated to produce serum levels of 10 - 20 micrograms/mL ) were compared in a double-blind , placebo-controlled crossover study in 21 patients with stable , chronic obstructive pulmonary disease .  Mean peak forced expiratory volume in 1 second ( FEV1 ) increases over baseline and the proportion of patients attaining at least a 15 % increase in the FEV1 ( responders ) were 31 % and 90 % , respectively , for ipratropium and 17 % and 50 % , respectively , for theophylline . The average FEV1 increases during the 6-hour observation period were 18 % for ipratropium and 8 % for theophylline . The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline . While side effects were rare , those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems . These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction 1 . The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol , 375 mg oral theophylline and both drugs in combination were compared in a r and omized , placebo-controlled , double-blind trial in eight patients with chronic , partially reversible airways obstruction . 2 . The four treatments were ( i ) oral theophylline , placebo aerosol ( TP ) ; ( ii ) oral placebo , rimiterol aerosol ( PR ) ; ( iii ) oral theophylline , rimiterol aerosol ( TR ) and ; ( iv ) oral placebo , placebo aerosol ( PP ) . The aerosol was administered 2 h after the oral treatment . 3 . Significant bronchodilatation ( % FEV1 change from control ) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min , whereas with PR only for 45 min ( P less than 0.05 ) . 4 . The mean , peak % FEV1 increases from control were 51.8 % at 125 min , 31.7 % at 125 min , 26.1 % at 210 min and 0.9 % at 30 min for TR , PR , TP and PP respectively . 5 . At 125 min ( 5 min after aerosol inhalation ) the mean % FEV1 change from control with TR ( 51.8 % ) Was significantly greater than with PR ( 31.7 % ) , TP ( 22.2 % ) ( P less than 0.05 ) and PP ( -2.4 % ) ( P less than 0.01 ) . 6 . The mean , peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively . Theophylline half-life ranged between 4.3 and 12.5 h ( mean + /- s.e . mean , 8.0 + /- 0.8 h ) . 7 . Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved STUDY OBJECTIVE To compare quality of life and exercise capacity ( primary aim ) , and drug usage ( secondary aim ) , between groups of patients with irreversible chronic airflow limitation ( CAL ) who were undergoing theophylline Theo-Dur ; Key Pharmaceuticals ; Kenilworth , NJ ) therapy guided by n of 1 trials or st and ard practice . DESIGN R and omized study of n of 1 trials vs st and ard practice . SETTING Outpatient departments in two tertiary care centers . PATIENTS Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators , and who were unsure whether theophylline was helping them following open treatment , were r and omized into n of 1 trials ( N=34 ) or st and ard practice . INTERVENTIONS The n of 1 trials ( single-patient , r and omized , double-blind , multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo ) followed published guidelines . St and ard practice patients stopped taking theophylline but resumed it if their dyspnea worsened . If their dyspnea then improved , theophylline was continued . In both groups , a decision about continuing or stopping the use of theophylline was made within 3 months of r and omization . MEASUREMENTS AND RESULTS The primary outcomes ( the chronic respiratory disease question naire [ CRQ ] and 6-min walk ) were measured at baseline , 6 months , and 12 months by personnel blinded to treatment group allocation . No between-group differences ( n of 1 minus st and ard practice ) were seen in within-group changes over time ( 1 year minus baseline ) in the CRQ Physical Function score ( point estimate on the difference , -2.8 ; 95 % confidence limits [ CLs ] , -8.2 , 2.5 ) , CRQ Emotional Function score ( point estimate on the difference , 0.5 ; 95 % CLs , -4.7 , 5.7 ) , or 6-min walk ( point estimate on the difference , 8 m ; 95 % CLs , -26 , 44 m ) . No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months . In 7 of 34 n of 1 trial patients ( 21 % ) , dyspnea improved during theophylline treatment compared with placebo treatment . CONCLUSIONS Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity , or reduce drug usa e , over 1 year compared to st and ard practice . Under the objective conditions of an n of 1 trial , 21 % of patients with CAL responded to theophylline . There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators , but the use of n of 1 trials to guide this decision did not yield clinical ly important advantages over st and ard practice Twenty-one patients with chronic bronchitis entered a double-blind , cross-over study in which they received sustained-release theophylline ( ' Nuelin'SA ) 350 mg daily for 4 days followed by 700 mg daily for 4 days and matching placebo tablets for 8 days with one week separation . Seventeen patients completed the study . Three patients receiving higher doses for weight than the mean for the group were withdrawn because of side-effects . Mild side-effects only were reported in six other patients . Theophylline given twice daily produced a steady-state mean serum concentration of 13.9 micrograms/ml , 13 patients having concentrations inthe range of 10 - 20 micrograms/ml . There was no demonstrable improvement of symptoms but pulmonary function measurements in the clinic at the end of active treatment showed a statistically significant improvement in PEFR , 1-second forced expiratory volume and forced vital capacity In a single-blind crossover study , two slow release theophylline preparations were evaluated in 18 patients with chronic bronchitis or asthma without cardiac , renal or liver disease . After r and omization into two groups , patients were treated , in a crossover study design , with 600 mg choline theophyllinate or 300 mg anhydrous theophylline administered orally every 12 h for 7 days . A 2-day washout period separated the two periods of treatment evaluation . Blood sample s in which plasma theophylline concentration was to be measured were taken at 7.30 a.m. , 2.00 p.m. and 7.30 p.m. during the last 5 days of therapy with each drug . The mean fluctuation in plasma theophylline concentration was ≤40 % in all 18 patients taking choline theophyllinate yet in only 15 ( 83 % ) patients administered anhydrous theophylline . Salbutamol inhaler was more frequently required for the relief of bronchospasm when taking anhydrous theophylline than when taking choline theophyllinate ( total of 41 vs 25 puffs , respectively , over 7 days ) . Drug-related adverse reactions occurred in four patients while taking anhydrous theophylline and in one patient while taking choline theophyllinate Enprofylline , a recently developed xanthine derivative , is a more potent bronchodilator than theophylline . This study compares the efficacy and safety of enprofylline with theophylline for chronic obstructive airways disease ( COAD ) in elderly subjects . The study was of a r and omized double-blind parallel design and commenced with a 1-week reference period when oral bronchodilators were withdrawn . Patients were then treated with either enprofylline or theophylline 150 mg bd for 2 weeks ( period 1 ) followed by 300 mg bd for a further 3 weeks ( period 2 ) . Patients recorded peak expiratory flow rate ( PEFR ) and adverse experiences , if any , in a diary , daily . Of 111 patients recruited for the study , 85 entered active treatment ( theophylline , n = 44 ; enprofylline , n = 41 ) . Mean age was 72 years and mean bronchodilator reversibility was 22 % .  Enprofylline increased mean morning PEFR by 11 % ( period 1 ) and 19 % ( period 2 ) whereas theophylline increased PEFR by 13 % and 19 % , respectively . From the enprofylline group 29 % were withdrawn from the study due mainly to headache and nausea/vomiting and from the theophylline group 7 % were withdrawn due mainly to nausea/vomiting . Mean plasma concentrations of enprofylline were 2.0 mg l-1 and 3.4 mg l-1 , and with theophylline 5.4 mg l-1 and 10.0 mg l-1 at the end of periods 1 and 2 , respectively . Enprofylline and theophylline produced similar improvements in lung functions and symptoms of chronic obstructive airways disease , but enprofylline was less well tolerated than theophylline Fourteen patients with chronic obstructive airway disease participated in a r and omized , double-blind , placebo controlled , cross-over study to assess the effect of acutely administered aminophylline on respiratory muscle strength and exercise tolerance . An increase in the distance walked in 6 min occurred following aminophylline ( p less than 0.01 ) . There was no improvement in respiratory muscle strength , assessed by maximal static mouth pressures , and no increase in maximal ventilation or oxygen uptake during a progressive exercise test . The ventilatory response to inhaled CO2 was increased ( p less than 0.02 ) , suggesting a central stimulatory effect of aminophylline . The mean increase in walking distance was 5.7 % . In most cases , the change was small and unlikely to be of practical benefit OBJECTIVE To assess the role of aminophylline in the treatment of acute exacerbations of bronchospastic disease when used in addition to inhaled beta-agonists and intravenous corticosteroids . DESIGN R and omized , double-blind , placebo-controlled intervention study . PATIENTS One hundred thirty-three adult patients with either asthma or chronic obstructive pulmonary disease who presented to the emergency department with asthma or wheezing . INTERVENTIONS All patients received therapy with both aerosolized metaproterenol and intravenous methyl-prednisolone . Patients were r and omly assigned to receive either a loading dose of aminophylline followed by a routine infusion ( n = 65 ) or an equal volume of placebo as a loading dose and infusion ( n = 68 ) . MEASUREMENTS AND MAIN RESULTS At discharge from the emergency department , the median serum theophylline concentration for the aminophylline group was 54 mumol/L ( 9.7 mg/L ) . The two groups showed no differences ( P greater than 0.2 ) in measurements of forced expiratory volume at 1 second ( FEV1 ) , forced vital capacity ( FVC ) , or peak expiratory flow rate ( PEFR ) at baseline or at 60 or 120 minutes after aminophylline administration . Neither patient satisfaction nor physician assessment of response to therapy differed between the two groups . There was no difference ( P greater than 0.2 ) in the frequency of side effects , except for a trend toward a higher frequency of nausea ( P = 0.13 ) in the aminophylline group . There was , however , a threefold decrease in the hospital admission rate for patients treated with aminophylline ( 6 % ) compared with placebo recipients ( 21 % ) ( P = 0.016 ) . CONCLUSION Aminophylline , in doses producing levels just below the commonly accepted therapeutic range , appears to decrease hospital admissions in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease . This finding , if confirmed in larger studies , may represent a substantial cost savings Thirteen clinical ly stable male patients aged 63 + /- 3 years with irreversible airway disease were given aminophylline and placebo in a r and omized crossover fashion on two consecutive days while receiving beta-agonists . During incremental exercise the maximal heart rate ( 139.0 + /- 22.1 vs 128.0 + /- 16.4 beats per minute ) and minute ventilation ( 41.9 + /- 6.9 vs 38.1 + /- 8.2 L/min ) were significantly higher and the arterial carbon dioxide pressure ( 34.6 + /- 5.0 vs 38.6 + /- 7.7 mm Hg ) was significantly lower during aminophylline administration than during placebo administration . However , spirometric findings , maximal inspiratory pressures , maximal oxygen consumption , work rate , and arterial oxygen pressure were similar on both regimens . We concluded that the major effect of aminophylline is to increase ventilatory drive in patients with irreversible airway obstruction . Unless an objective change in spirometric data or exercise capacity can be documented , we believe that aminophylline therapy is not warranted in these patients To investigate the additive effect of oral theophylline on combined inhaled anticholinergic agent and beta 2-agonist therapy , 12 patients with stable COPD ( 64.6 + /- 5.9 years ) completed a r and omized , double-blind placebo-controlled crossover trial of oral theophylline for a 4-week period ( 400 mg for 2 weeks , followed by 600 mg for 2 weeks ) . All of the patients continued to inhale both salbutamol , 200 micrograms , and ipratropium bromide , 40 micrograms , using a metered-dose inhaler four times a day .  Spirometry  was assessed before , and 15 and 60 min after the inhalation of bronchodilators at 2-week intervals . Even after the inhalation of salbutamol and ipratropium , theophylline significantly improved FEV1 and daily peak expiratory flow rate compared with the placebo . No significant improvement in the daily symptom scores for cough , sputum , wheezing , or shortness of breath was observed throughout the different phases of treatment . This study shows that the additive bronchodilating effect of theophylline , when used in combination with salbutamol , 200 micrograms , and ipratropium , 40 micrograms , is significant but small in stable COPD . The addition of theophylline did not significantly improve the patient 's symptoms . Oral theophylline , when used in combination with an inhaled anticholinergic agent and an inhaled beta 2-agonist , may be of limited value in the treatment of stable COPD Oxygen desaturation and sub clinical coronary artery disease may predispose older patients with chronic airflow obstruction to cardiac arrhythmias , especially when high concentrations of theophylline are present in the blood . To assess the safety and efficacy of Uniphyl tablets , an oral theophylline preparation formulated for once-daily dosing , in elderly patients with chronic airflow obstruction , we conducted a r and omized , three-phase , double-blind crossover study comparing evening dosing with Uniphyl tablets , Theo-Dur tablets administered twice daily , and placebo . The patients in the study were scheduled to receive each treatment for two weeks . Each day , symptoms , side effects , peak expiratory flow rates , and use of metered-dose inhalers were recorded . Near the end of each phase , serum theophylline concentrations were measured every two hours between 8:00 A.M. and 8:00 P.M. on two consecutive days . The patients underwent ambulatory Holter monitoring during the final 48 hours of each phase . Twelve patients completed the active-drug phases of the study , but seven of the 12 were removed from the placebo phase because of increasing symptom severity . The difference between the number of patients completing the active-drug and placebo phases was statistically significant ( p less than 0.001 ) . Treatment with Uniphyl tablets result ed in a significantly ( p less than 0.05 ) greater increase in peak expiratory flow rate than Theo-Dur tablet therapy , and both active drugs increased peak expiratory flow rate more than placebo .  Circadian variation in peak expiratory flow rate was seen during the placebo and Theo-Dur tablet phases but not during the Uniphyl tablet phase . Symptoms and side effects were similar during the two active-drug phases . Cardiac ectopy was observed in most of the patients , but it was not significantly greater during the theophylline phases than during the placebo phase . Furthermore , ectopic activity was not directly related to the times of maximal serum theophylline concentration To evaluate the role of inhaled ipratropium bromide alone vs oral theophylline plus inhaled beta-agonist or the combination of all three in patients with stable COPD , the following double-blind , placebo-controlled study was conducted . Forty-eight patients with stable COPD ( mean age , 61.8 years , with mean baseline FEV1 < 1.0 L ) were r and omized on four separate days to receive the following drug regimens : ( 1 ) theophylline tablets ( dose previously determined to result in blood level of 12 to 18 mg/L ) , followed by inhaled albuterol ( 2 puffs via metered-dose inhaler [ MDI ] ) , followed by inhaled placebo ( 2 puffs via MDI ) ; ( 2 ) oral placebo followed by ipratropium ( 2 puffs via MDI ; 36 micrograms ) , followed by inhaled placebo ; ( 3 ) oral theophylline , followed by albuterol , followed by ipratropium ; or ( 4 ) oral placebo followed by two inhaled placebos . On study days , spirometry and heart rate were measured at time 0 , 30 min , 60 min , and hourly for 6 h. The FEV1 peak change ( liters ) and area under the curve ( liter x hours ) for the treatment groups were compared . Ipratropium was more effective than placebo ( p = 0.001 and p = 0.0078 , respectively ) . The combination of albuterol and theophylline was superior to ipratropium alone ( p = 0.001 and p = 0.0001 , respectively ) , and all three drugs together were superior to the combination of albuterol and theophylline ( p = 0.0373 and p = 0.0289 ) , respectively ; one-sided test of hypotheses ) . Peak heart rates were significantly higher for treatment groups compared with placebo groups ( p = 0.0001 ) . However , theophylline and albuterol and the combination of all three drugs result ed in greater peak heart rates than did ipratropium alone ( p = 0.001 ) . These data suggest that for patients with stable COPD , combination therapy with ipratropium ( two puffs ) , theophylline , and albuterol ( two puffs ) is superior to ipratropium alone or the combination of theophylline and albuterol Abstract Physiologic responses to intravenously administered theophylline were determined in nine hospitalized asthmatic subjects . In each patient incremental theophylline plasma concentration plateaus were attained at which pulmonary-function changes related to drug administration were examined . Continuous improvement in vital capacity and first-second forced expiratory volume was observed over the plasma range of theophylline concentration of 5 to 20 mg per liter . The improvement varied directly with the logarithm of the plasma concentration . A safe and effective dosage regimen for intravenous theophylline can be based on these observations . After a loading dose of aminophylline , 5.6 mg per kilogram given intravenously , 0.9 mg per kilogram per hour can be given as a maintenance dose . This amount will result in a plasma theophylline concentration of approximately 10 mg per liter for 95 per cent of patients and in recovery from some 30 to 40 per cent of reversible pulmonary-airway obstruction . ( N Engl J M This study sought answers to 2 questions : ( 1 ) Is severe dyspnea to the point of exhaustion regularly accompanied by diaphragmatic fatigue in patients with moderately severe chronic obstructive pulmonary disease ( COPD ) ? ( 2 ) When diaphragmatic fatigue occurs in such patients , does theophylline prevent or delay its onset ? Eight eucapnic patients with moderately severe COPD were subjected to 2 different stresses to the point of severe dyspnea requiring cessation of the stress . The stresses were cycle exercise and inspiratory resistive breathing , the latter requiring a tidal Pdi equal to 60 % of Pdimax . Despite incapacitating dyspnea , objective evidence of diaphragmatic fatigue was not encountered during cycle exercise . During inspiratory resistive breathing , diaphragmatic fatigue was encountered in all patients as defined by consistent inability to attain a target Pdi during final moments of the resistance run . Patients were uniformly extremely dyspneic  at this point . In neither stressful maneuver did oral sustained-release theophylline show a convincing or significant advantage over placebo when administered in a r and omized double-blind crossover protocol . These results suggest that the diaphragmatic fatigue encountered in this sort of COPD patient may be of predominantly central rather than peripheral ( myogenic ) origin and that theophylline may not be effective in this type of fatigue Effects of theophylline administration on the respiratory drive were studied in seven patients with chronic obstructive pulmonary disease ( COPD ) .  End tidal CO2 ( PetCO2 ) , minute ventilation ( Ve ) , forced expiratory volume in one second ( FEV1 ) , forced vital capacity ( FVC ) , oxygen consumption ( VO2 ) , carbon dioxide output ( VCO2 ) , serum theophylline level ( STL ) , ventilatory response ( VeR ) , and mouth occlusion pressure response ( OPR ) to rise in PetCO2 on rebreathing were measured before and at 2-hour intervals after oral administration of 5 mg/kg anydrous theophylline or placebo .  Mouth occlusion pressure response and VeR showed c significant increase after theophylline but not after placebo . Significant positive correlation between changes ( delta ) in STL and OPR ( delta OPR = 0.025 + 0.8 delta STL ; SEE = 1 ; r = 0.4 ; P < 0.005 ) and between STL and VeR ( VeR = 0.82 + 0.055 STL + /- SEE = 0.7 ; r = 0.46 ; P < 0.01 ) and an inverse correlation between delta STL and delta PetCO2 ( delta PetCO2 = 13.8 - 0.59 delta STL ; SEE = 9.1 ; r = 0.61 ; P < 0.001 ) were noted . There was no correlation between the indices of respiratory drive and FEV1 , Ve , VO2 , or VCO2 . It is concluded that theophylline increases respiratory drive in clinical ly employed doses independently of its bronchodilator or metabolic effects Even though the clinical efficacy is not well established , theophylline is commonly prescribed as a second or third line drug after inhaled beta 2-agonists and corticosteroids for patients with chronic obstructive pulmonary disease ( COPD ) . The therapeutic index is narrow , and therefore theophylline is often given in a " safe st and ard dose " , e.g. 300 mg b.i.d . We studied the long-term effect of sustained-release theophylline 300 mg b.i.d . over four weeks in 48 patients with severe irreversible COPD ( FEV1 : 0.99 + /- 0.45 l , FVC : 2.21 + /- 0.68 l ) in a r and omized , double-blind crossover study . During theophylline treatment there was significant improvements in dyspnoea score ( p < 0.001 ) and morning peak-flow ( p < 0.05 ) . In spite of this , there was no significant change in the patients ' " sense of well-being " or their daily use of inhaled beta-agonist . Spirometric tests or arterial blood gas values did not change significantly either . It is concluded that addition of theophylline in a " safe st and ard dose " ( i.e. 300 mg b.i.d . ) has only limited value in these patients
BACKGROUND Oral theophylline has , for many years , been used as a bronchodilator in patients with COPD .
Despite the introduction of new drugs , and its narrow therapeutic index , theophylline is still recommended for COPD treatment .
OBJECTIVES To determine the effectiveness of oral theophylline when compared to placebo in patients with stable COPD .