Treatment of chronic obstructive pulmonary disease with orally administered theophylline. A double-blind, controlled study. Efficacy of theophylline in "irreversible" airflow obstruction. Effects of theophylline on plasma levels of interleukin-4, cyclic nucleotides and pulmonary functions in patients with chronic obstructive pulmonary disease Effect of theophylline in chronic obstructive lung disease. The Usefulness of Theophylline in Nonasthmatic Airway Obstruction The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD. Dose response relation to oral theophylline in severe chronic obstructive airways 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. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Randomised controlled trial of aminophylline for severe acute asthma Does inhaled albuterol improve diaphragmatic contractility in patients with chronic obstructive pulmonary disease? Theophylline improves measurements of respiratory muscle efficiency. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic 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. Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. Effect of low-dose theophylline on airway inflammation in COPD. Sustained-release theophylline in chronic bronchitis. Aminophylline, respiratory muscle strength and exercise tolerance in chronic obstructive airway disease. Aminophylline therapy for acute bronchospastic disease in the emergency room. 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. 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 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 Summary In order to measure the plasma levels of interleukin-4 ( IL-4 ) . cyclic adenosine monophosphate ( cAMP ) and cyclic guanosine monophosphate ( cGMP ) in patients with chronic obstructive pulmonary disease ( COPD ) and observe the effects of oral theophylline on them , we divided 28 COPD patients into COPD experimental group and COPD control group .  Plasma levels of IL-4 , cAMP and cGMP as well as parameters of pulmonary function tests were measured in these 2 groups before and after 2 weeks of treatment with oral theophylline ( Protheo , 400 mg , qd ) or placebo .  Plasma levels of IL-4 and cGMP were significantly elevated in patients with COPD as compared with normal controls ( P < 0 . 05 ) , while cAMP and cAMP/cGMP were significantly lower than those in controls ( P < 0 . 01 ) . Plasma level of IL-4 was inversely correlated with forced expiratory volume at the first second ( FEV1 ) and with maximum expiratory flow rate at 50 % of forced vital capacity ( V50 ) ( bothr= −0.46,P < 0.05 ) while it was directly correlated with the scores of the clinical manifestations ( r=0.57,P < 0.05 ) in COPD patients . Two weeks after treatment with theophylline , IL-4 and cGMP in COPD experimental group were decreased significantly while cAMP and cAMP/ cGMP increased significantly ( P < 0 . 05 ) . The change of IL-4 was inversely correlated with the changes of FEV1 , and V50(r=−0.53 and -0.54 , respectively , P < 0 . 05 ) . Two weeks after placebo treatment , the COPD control group did not show such changes . We are led to conclude that IL-4 might play a role in the pathogenesis of the airway inflammation and air flow limitation in COPD patients and the mechanisms of theophylline ’s therapeutic efrects of attenuating air-flow limitation may partially depend on its anti-inflammatory effects on the airways which , in turn , is dependent on its inhibitory effects on some inflammatory mediators such as IL-4 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 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 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 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 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 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 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 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 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 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 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 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 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 OBJECTIVE Recent studies have shown that theophylline may exert anti-inflammatory effects on neutrophils . We undertook to assess the effect of theophylline on airway inflammation in COPD . METHODOLOGY We performed a 4-week r and omized double-blind , placebo-controlled study in 11 theophylline-naive patients with mild to moderate COPD . After a 1-week run-in period , six subjects were administered 400 mg/day theophylline ( Theodur ; Nikken Chemicals Co. Ltd , Tokyo , Japan ) for 4 weeks , while five subjects were administered a placebo .  Induced sputum was obtained before and after the run-in period and then after 2 and 4 weeks of treatment . Cell differential count and levels of interleukin-8 , matrix metalloproteinase-9 , neutrophil elastase ( NE ) , myeloperoxidase ( MPO ) , alpha1-antitrypsin ( alpha1-AT ) , leukotriene B4 and tissue inhibitor of metalloproteinases-1 ( TIMP-1 ) were assessed . RESULTS No variable was significantly different during the run-in period or with placebo treatment . In contrast , theophylline treatment significantly decreased NE and MPO levels at 4 weeks , although the cell differential count did not change appreciably as a result of treatment . CONCLUSION These results suggest that 4 weeks of theophylline treatment attenuates neutrophil-associated inflammation in the airways of mild to moderate COPD patients . However , the clinical benefits remain to be determined 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 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 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 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
PURPOSE OF REVIEW The role of theophylline in the management of chronic obstructive pulmonary disease remains controversial .
This review was undertaken to determine the efficacy of theophylline in patients with stable disease .