Theophylline and salbutamol improve pulmonary function in patients with irreversible chronic obstructive pulmonary disease. 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 theophylline on exercise performance in patients with severe chronic obstructive pulmonary disease. The usefulness of theophylline in nonasthmatic airway obstruction. Physiological and neuropsychological effects of theophylline in chronic obstructive pulmonary disease. The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD. Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease. Long-term, double-blind comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and adults with asthma.
To investigate the efficacy of bronchodilators in patients with irreversible chronic obstructive pulmonary disease (COPD), we conducted a double-blind, randomized, 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 resulted 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. 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 randomized, 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 standard 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 resulted 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 clinically significant benefits in patients with severe COPD. To assess the effects of theophylline in chronic obstructive pulmonary disease, we conducted a randomized, 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 random 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. 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.
                A randomised, 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 random 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.
                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.
                Theophylline improved cardiorespiratory performance in these patients with severe chronic obstructive pulmonary disease mainly by increasing the ventilatory capacity. This study evaluated the effectivness of oral bronchodilator therapy using theophylline in patients with nonreversible chronic obstructive pulmonary disease. 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. Clinically, 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 clinically during theophylline therapy whereas their pulmonary function may deteriorate during placebo therapy. 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 randomized 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. 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.
                Twenty-four male patients with stable COPD (FEV1, 0.96 +/- 0.43 L; 36.8 +/- 17.0 percent predicted [% pred]) completed a randomized, double-blind, placebo-controlled crossover trial with oral theophylline for 4 weeks.
                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).
                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. Often chronic obstructive pulmonary disease (COPD) patients treated for acute exacerbations receive intravenous (IV) aminophylline in addition to inhaled bronchodilators that may raise serum levels of theophylline into the toxic range. A double-blind, randomized study of 52 men with COPD who came to the emergency department for treatment of exacerbations was initiated to establish the efficacy and safety of this common practice. After history and physical examination, patients were treated with 28% oxygen by Venturi mask and 0.3 cc metaproterenol sulfate in 2.5 cc saline by nebulizer; an IV line was started and patients received either aminophylline or D5W. Measurements included baseline and two-hour serum theophylline levels, pulmonary function tests, and symptom questionnaires. Mean values from the entire group showed decreases in respiratory rate, cardiac rate, and pulsus paradoxus, and increases in forced expiratory volume in one second (FEV1) and vital capacity (VC) over a two-hour treatment period (P less than .01). Despite the increase in serum theophylline in the treatment group, the demographic, clinical, pulmonary function, and outcome data were found to have no statistically significant differences when compared to control patients. The data were then analyzed according to serum theophylline levels. Theophylline level greater than 20 micrograms/mL occurred in 15 patients with no untoward effects; premature ventricular contractions (PVCs) were no more frequent in this group than in those with lower serum theophylline levels. A theophylline level greater than 10 micrograms/mL after two hours of treatment resulted in the following differences, which were not statistically significant: mean FEV1 response less than or equal to 10 micrograms/mL vs greater than 10 micrograms/mL, 20% vs 28%; mean VC change, 17% vs 30%; or mean emergency department returns in one week, 0.1 vs 0.26. In our experience, oxygen and inhaled metaproterenol are effective treatment for exacerbations of COPD. This parallel-group study compared the safety and efficacy of controlled-release albuterol versus sustained-release theophylline, both administered every 12 hours. One hundred twenty-four adolescent and adult patients with asthma and with chronic reversible obstructive airway disease were studied. All patients qualified with an FEV1 less than or equal to 80% of predicted (not receiving treatment) and greater than or equal to 15% reversibility in FEV1 or greater than or equal to 25% reversibility in FEF25-75% after inhaled isoproterenol. All patients were known to be able to take theophylline without unacceptable adverse effects. Theophylline was titrated for patients to receive, unblinded, theophylline serum concentrations of 10 to 20 micrograms/ml. With subsequent randomization, 62 patients continued to receive theophylline and 62 patients started taking albuterol in the 12-week, double-blind, double-dummy portion of the study. Pulmonary function was measured during a pretreatment visit (unmedicated) and serial assessment was made starting just before the morning dose and continuing for 12 hours after the dose at the end of 1, 6, and 12 weeks of treatment. Both treatment groups exhibited statistically significant increases in FEV1 from the pretreatment visit to all times of observation at weeks 1, 6, and 12. The increases in FEV1 were not significantly different between albuterol and theophylline administration. There was no evidence of tolerance to the bronchodilatory effect during 12 weeks in either treatment group. Only one patient in the study stopped treatment because of an adverse effect. This patient had tremor during albuterol administration. All other adverse events were tolerated or resolved during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Theophylline has a modest effect on FEV1 and FVC and slightly improves arterial blood gas tensions in moderate to severe COPD. These benefits were seen in participants receiving a variety of different concomitant therapies. Improvement in exercise performance depended on the method of testing. There was a very low dropout rate in the studies that could be included in this review, which suggests that recruited participants may have been known by the investigators to be theophylline tolerant . This may limit the generalisability of these studies.