Behavior abnormalities and poor school performance due to oral theophylline use. Comparison of the long-term effect of fenoterol hydrobromide and theophylline syrups in pre-school asthmatic children. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. A comparative trial of slow-release aminophylline, salbutamol and a half dose combination in the prevention of childhood asthma. Once daily theophylline in childhood asthma. A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children. Study of the effects of treatment with theophylline on the cognitive process and behaviour of children with bronchial asthma. Comparison of nebulised sodium cromoglycate and oral theophylline in controlling symptoms of chronic asthma in pre-school children: a double blind study. Extrapulmonary effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma. Nocturnal wheezing in children: management with controlled-release aminophylline. Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. A collaborative study. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. The value of maintenance theophylline in steroid-dependent asthma. Comparison of orally administered metaproterenol and theophylline in the control of chronic asthma. Nebulised cromoglycate, theophylline, and placebo in preschool asthmatic children. Slow-release terbutaline and theophylline for the long-term therapy of children with asthma: a Latin square and factorial study of drug effects and interactions. A double-blind study comparing the effectiveness of cromolyn sodium and sustained-release theophylline in childhood asthma. Choline theophyllinate in children with asthma: a controlled trial. Salmeterol versus theophylline in the treatment of asthma. Monitoring response to bronchodilator therapy in asthma in childhood. Fluticasone propionate compared with theophylline for mild-to-moderate asthma. Slow release theophylline in preschool asthmatics. Administration of half-dose theophylline together with ketotifen to asthmatic children--a double-blind, placebo-controlled study. Long-term treatment of children with sustained-release theophylline. A once daily theophylline preparation in prevention of nocturnal symptoms in childhood asthma. Controlled trial of cromoglycate and slow-release aminophylline in perennial childhood asthma. Long-term, double-blind comparison of controlled-release albuterol versus sustained-release theophylline in adolescents and adults with asthma. A controlled comparison of slow-release theophylline, ketotifen and placebo in the prophylaxis of asthma in young children. A comparison of metaproterenol and theophylline for control of childhood asthma. Need for theophylline in severe steroid-requiring asthmatics.
Studies evaluating adverse effects of oral theophylline on learning and behavior have been performed on children with asthma receiving long-term theophylline therapy. To further differentiate the effects of asthma itself from the drugs used, we evaluated 20 asthmatic children (6 to 12 years of age) who had not received oral bronchodilators for at least 6 months. A double blind, placebo-controlled, parallel format was used with a 4-week theophylline or placebo period preceded by a 2-week baseline. Theophylline serum levels were maintained between 10 to 20 micrograms/mL. During baseline and treatment periods, the child's home and school behavior/performance were monitored independently by their parents and teachers using standardized report forms. A battery of psychologic tests was administered at the end of baseline and treatment periods. Seven children receiving theophylline were noted to have a change in school behavior and/or performance during their 4 weeks on drug compared to baseline, whereas none of the children receiving placebo were noted to be different (P = .004). Thus, the short-term administration of theophylline to asymptomatic asthmatic children not receiving oral bronchodilators can adversely affect school performance and behavior. Because this population represents the majority of asthmatic children, one needs to use theophylline cautiously in this age group, monitor school performance closely, or seek other treatment modalities. Eleven asthmatic children less than six years were treated double-blind for eight weeks with fenoterol, theophylline or placebo syrups. Both active drugs significantly decreased the incidence of cough compared to placebo. Nocturnal symptoms and wheezes were also reduced but were not improved to a statistically significant degree. Inhaled corticosteroids and oral theophylline are effective treatments for moderate asthma.
                We sought to compare the benefits and adverse reactions of theophylline and aerosol beclomethasone spray.
                A multicenter, double-blind, double-placebo, randomized, controlled trial of 1-year duration was performed. Seven hundred forty-seven patients with asthma received either beclomethasone dipropionate aerosol spray (84 microg four times per day) or sustained-release theophylline twice per day in doses adjusted for optimum control of the disease. The main outcome measures were daily diary of symptoms and peak flow rates (recorded on a mark-sense computer-readable form); supplemental bronchodilator use; doctor's office or hospital visits and absence from work or school; spirometry; methacholine testing; adverse experiences; and cortisol blood measurements.
                Both treatment strategies reduced symptoms promptly and achieved low absenteeism from work or school and low rates of emergency treatment for asthma. Both maintained nearly normal pulmonary function. Beclomethasone was statistically significantly more effective in reducing symptoms, supplemental bronchodilator and systemic glucocorticoid doses, bronchial hyperresponsiveness, and eosinophilia. However, the magnitude of these differences was small. Theophylline caused more headache, nervousness, insomnia, and gastrointestinal distress, and more patients discontinued treatment because of side effects. Beclomethasone caused more oropharyngeal candidiases and hoarseness and reduced morning plasma cortisol levels before and after cosyntropin. It reduced the rate of growth in children. No new cataracts or glaucoma developed.
                Theophylline effectively controlled symptoms at lower than the customarily recommended blood level. The risk/ benefit profiles of these agents suggest that inhaled corticosteroids may be the preferred agent for most adult patients and for some children. The effect of slow-release aminophylline, salbutamol and a half dose combination of both was compared in children with chronic asthma. Drugs were given over three consecutive 5-week periods during which patients recorded daily peak flow measurements and symptom scores. At the end of each treatment period pulmonary function tests were done. Sixteen of twenty-nine children completed the trial satisfactorily and their results have been used for analysis. The data show slow-release aminophylline and salbutamol to be equally effective and the half dose combination as effective as either drug alone. The results suggest there may be a therapeutic advantage in combining a beta 2 agonist with theophylline when high doses of either drug alone are not fully effective or when toxic effects occur. A new sustained-release theophylline preparation has been designed with the purpose of providing 24-hour protection against bronchospasm in asthmatics when given as a single dose. Fifteen children with moderate asthma completed a double-blind, placebo-controlled crossover trial of this product given once a day before bed. There was a significant fall in night symptoms (P less than 0.05), a rise in the mean early morning peak expiratory flow rate (PEFR) (P less than 0.01) and a fall in the number of mornings on which PEFR was less than 2 SD under the mean for height (P less than 0.01). An improvement in mean day symptom scores and evening PEFR was not significant. Thus we have shown that this product given once a day before bed is suitable for this way. Inhaled corticosteroids (ICSs) are widely used in combination with other classes of drugs for treatment of childhood asthma. The efficacy and the safety of montelukast added to low-dose ICS therapy were compared with those of sustained-release theophylline added to low-dose ICS therapy in asthmatic children in the present study.
                Following the 2-week run-in period, 6-to 14-year old patients receiving treatment with ICSs were randomized to treatment for 4 weeks with either montelukast 5 mg once daily or sustained release theophylline 5-8 mg/kg (dry syrup) or 100-200 mg (tablet) twice daily. Patients also received a fixed dose of ICS throughout the run-in and treatment periods. The primary efficacy endpoint was the change from baseline in peak expiratory flow (PEF) at Week 2.
                A significant increase in morning PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 2 (change from baseline of 22.8 L/minvs. 8.7 L/min; p = 0.041 for between-group difference) and at Week 4 (31.0 L/minvs. 9.8 L/min; p = 0.012). A significant increase in evening PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 4 (24.7 L/minvs. 8.7 L/min; p = 0.027). There were no significant differences between the treatment groups in incidences of clinical and laboratory adverse experiences.
                The results indicate that montelukast added to low-dose ICS is an effective and safe option for the treatment of asthma in children. The effects of theophylline (T) on cognitive and emotional aspects were evaluated in nine children with mild bronchial asthma (7-14 years). The study was double blind crossover against placebo (P) for a period of 30 days for each. The children admitted to the study had an average IQ (80-101) and were able to perform pulmonary function studies (PFS). On days 0, 30 and 60 patients were evaluated by psychological tests (Wisc, Bender, Complex Figure A. Rey and Miss Goodenough/Machouver). PPS an T serum levels were performed on days 15 and 45. During the T period all patients had T serum levels greater than 5 mcg/ml (5 to 22). The final evaluation showed no changes in the psychological tests. Behaviour alterations were not reported by the parents. In conclusion, in this group of patients there was no influence of T on the asthmatic children's behavior. These results are in agreement with the recent data published by Schlieper et al. (J. Pediatr. 118: 449-455, 1991). The efficacy of nebulised sodium cromoglycate and an oral theophylline solution at currently recommended doses were compared in one to six-year-old children with chronic asthma. Twenty-six children completed a 24-week double-blind trial of treatment with sodium cromoglycate (SCG), theophylline and a combination of both. The three regimens were administered, each for eight weeks, in a random sequence. SCG was administered by inhalation as a nebulised solution in standard doses of 20 mg qid and serum drug concentrations were recorded. Theophylline was given as liquid aminophylline. Dosage was individualised with the assistance of serum theophylline measurements and averaged 6.1 mg/kg/dose q6h. Patients had an average of 61% symptom-free days while on SCG and combination regimens, compared with only 46.5% for days free of symptoms when on theophylline alone (p less than 0.05). There was significantly less use of supplementary medication for acute symptoms (p less than 0.05) when on the combination of SCG and theophylline. No regimen was more frequently associated with symptoms of exercise intolerance or decreased appetite. Numerous adverse side effects to theophylline were recorded, but none were recognised with SCG. SCG is at least as effective as theophylline in controlling asthmatic symptoms in the 1-6-year-old age group. The extrapulmonary effects of slow-release theophylline and an inhaled beta 2-agonist (albuterol) were examined separately and in combination among 18 adults and adolescents with asthma during a 3-month randomized, double-blind, crossover trial. Although neither global impressions nor daily diaries revealed differences in adverse effects, a structured questionnaire completed at the end of each regimen suggested a small but statistically significant increase in nausea and depressive and caffeine-like symptoms during the theophylline-containing regimens. Theophylline was also associated with improved verbal learning but decreased motor steadiness. Metabolic effects associated with theophylline included lower serum bicarbonate, greater urinary calcium excretion, and higher serum calcium, uric acid, and creatinine. Albuterol was associated with lower neutrophil counts and lower serum theophylline concentrations. There were no drug-induced effects on cardiac rhythm. nan 28 children with chronic asthma (15 in Denver and 13 in London) completed a 12 wk double-blind trial of treatment with sodium cromoglycate (cromolyn sodium), theophylline, and a combination of both. The three regimens were administered, each for 4 wk, in random sequence as part of a collaborative investigation of the relative efficacy of the two antiasthmatic agents. Cromoglycate was administered by inhalation in standard doses of 20 mg q.i.d. Theophylline dosage was individualized with the assistance of serum-theophylline measurements and averaged 6 mg/kg/dose q.i.d. (range 3-8--8-5 mg/kg/dose). Peak expiratory-flow rates measured twice daily on all patients averaged 75% of that predicted during cromoglycate administration, 79% during theophylline, and 81% during the combined-drug regimen (P less than 0.05). Patients had an average of 59% of days free of symptoms while on cromoglycate and 71% of days symptom-free when on both the theophylline and the combination regimens (P less than 0.025). None of the 13 patients whose asthmatic symptoms were previously controlled with cromoglycate was unable to complete the 4 wk trial with theophylline alone; 1 patient whose symptoms had been previously controlled with theophylline twice developed severe asthmatic symptoms while receiving cromoglycate, and he had to be withdrawn from that study period. No significant differences in adverse effects of the medication were observed during the 12 wk trial. To compare the benefits and adverse reactions of theophylline and beclomethasone (BDP) in the long-term control of mild to moderate chronic asthma in children.
                Multicentered, double-blind, double-placebo, randomized, controlled trial.
                One hundred ninety-five children between the ages of 6 and 16 years with mild to moderate asthma.
                Treatment with either BDP, 84 micrograms four times a day, or sustained-release theophylline administered twice daily in doses adjusted for optimum control of symptoms.
                Daily diary record of symptoms, peak flow rates, supplemental bronchodilator and glucocorticoid treatment, doctor and hospital visits, absence from work and school, and side effects.
                Aerosol BDP and sustained-release theophylline were effective primary treatments for mild to moderate chronic asthma. Beclomethasone resulted in comparable symptom control with less bronchodilator use and fewer courses of systemic steroids than did theophylline. Side effects were observed significantly more frequently with theophylline than with BDP. Growth velocity suppression was noted with BDP and was more pronounced in boys. Suppression was not associated with alterations in cortisol measurements either at baseline or following stimulation.
                Both theophylline and BDP are effective therapy for mild to moderate asthma. Caution must be used with the administration of BDP in children because of possible growth velocity suppression. We examined the value of maintenance theophylline at serum concentrations of 10 to 20 micrograms per milliliter in a placebo-controlled, randomized, double-blind trial of 33 children with steroid-dependent chronic asthma. Patients were free of all symptoms 63 +/- 6 per cent of the days (mean +/- S.E.M.) when taking theophylline as compared with 42 +/- 6 per cent when taking placebo (P < 0.01). Inhaled metaproterenol was required twice as often with placebo (P < 0.01), and additional daily corticosteroids were needed more than three times as often with placebo (P = 0.02). Daily peak flow measurements improved with theophylline (P < 0.01) as did monthly spirometric measurements and residual volume measured by plethysmography. Theophylline was associated with a 50 per cent increase in the number of patients able to complete an exercise test (P = 0.01) and with a smaller decrease in forced expiratory volume in one second among patients completing the exercise (P < 0.02). We conclude that maintenance bronchodilator therapy with theophylline can provide clinically important benefit for patients with chronic steroid-dependent asthma. The efficacy of metaproterenol (orciprenaline) and theophylline given orally at currently recommended doses was examined in 34 children with chronic asthma using a randomized double-blind cross-over evaluation of four weeks' duration for each active regimen. No serious adverse effects were seen with either medication, but tremor occurred more frequently with metaproterenol (P less than 0.01). No significant differences were observed in the frequency of nausea, vomiting, headache, or insomnia (P greater than 0.05). Symptoms of wheezing, coughing, exercise intolerance, and interference with sleep were more frequently associated with the oral metaproterenol regimen; completely asymptomatic days occurred 50% more frequently in association with theophylline therapy (P less than 0.01). Mean peak flows, performed twice daily during each of the four-week study periods, were 86 and 92% of predicted for metaproterenol and theophylline, respectively (P less than 0.05). Pulmonary function decreased significantly less with theophylline than with metaproterenol among those who completed six minutes of treadmill exercise during both regimens (P less than 0.05). Corticosteroids, used for acute symptoms that failed to respond to the addition of inhaled metaproterenol, were required in four patients during both regimens, in ten patients only during the metaproterenol regimen, and in one patient only during the theophylline regimen (P less than 0.02). Thus, theophylline therapy was associated with fewer adverse effects, fewer symptoms of asthma, better pulmonary function, better exercise tolerance, and less requirements for corticosteroids than was treatment with metaproterenol. Sixteen children aged under 5 years with chronic asthma completed a double-blind crossover trial of treatment with oral choline theophyllinate (6.7 mg/kg four times daily) and nebulised sodium cromoglycate (20 mg four times daily). The trial comprised three 8-week treatment periods during which active sodium cromoglycate, active choline theophyllinate, and placebo were given in random order. Symptom scores for sleep disturbance, cough, wheeze, and daily activities were similar during the three treatment periods if results were analysed using Friedman's non-parametric analysis of variance. However the Mantel-Haenszel test showed that sodium cromoglycate was superior to placebo (P less than 0.05) in maintaining normal daily activities. Either regimen is safe and well tolerated by young children. To evaluate the long-term effects of slow-release formulations of theophylline and terbutaline on pulmonary function, clinical symptoms, and side effects, 24 children with stable and moderately severe perennial asthma participated in a prospective double-blind cross-over study. The patients and the treatments were randomized according to the Latin square design to eliminate all possible period/climate biases throughout the protracted study period. The treatments consisted of terbutaline, 5 mg, theophylline, 200 mg, the combination, and placebo, given twice daily orally and crossing over every 28 days. The two drugs, administered alone or in combination, improved lung function and symptoms when compared with placebo. The interaction of theophylline and terbutaline was quantitatively shown by 2 x 2 factorial statistical design to be essentially additive rather than synergistic in the control of asthma. No increase in side effects was noted when the combined therapy was used. These findings suggest therapeutic advantages to combining submaximal oral doses of sustained-release theophylline and terbutaline for the long-term treatment of children with asthma. The effectiveness of cromolyn sodium and theophylline on asthma in children was compared during a 3-month trial. Forty-six children (aged 5 to 15 years) with asthma were assigned at random to cromolyn or theophylline (Theo-Dur) treatment groups. Each subject received theophylline placebo or cromolyn placebo in addition to the active drugs. A methacholine challenge test was done at the start of the study to document asthma and was repeated during the third month. The theophylline dosage was regulated to obtain serum levels of 10 to 15 micrograms/mL by a physician not involved directly with patient care. Forty patients completed the study. Both theophylline and cromolyn treatment groups showed improvement from base-line status in terms of symptom scores, pulmonary function, and decreased use of inhaled albuterol. Patients treated with theophylline had more side effects and required more frequent office visits than those treated with cromolyn. Both groups had decreased sensitivity to methacholine, and for one statistical test patients treated with cromolyn improved significantly. These results indicate that cromolyn is as effective as theophylline in treating mild to moderate asthma in children; additional benefits were fewer side effects and a possible decrease in bronchial hyperactivity. nan Although theophylline is recommended by current guidelines for the management of asthma in patients with persistent symptoms, theophylline has a narrow therapeutic index, requiring individual dose titration and regular monitoring of serum theophylline concentrations to avoid adverse effects.
                To compare the inhaled long-acting bronchodilator, salmeterol, with the oral bronchodilator, theophylline, in the maintenance treatment of asthma.
                In two multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group studies, patients received salmeterol aerosol 42 micrograms, extended-release theophylline capsules, or placebo twice daily for 12 weeks.
                Of 638 adult and adolescent patients with moderate asthma who entered the prebaseline theophylline titration period, 154 were withdrawn prior to randomization (71 due to theophylline-related adverse effects); 484 patients comprised the intent-to-treat population. The mean serum theophylline concentration measured approximately seven hours postdose during the titration period in the theophylline group was 12.7 mg/L (70 mumol/L). The same dose during the treatment period resulted in a mean serum theophylline concentration between 7.6 to 7.9 mg/L (42-44 mumol/L) when measured approximately 12 hours postdose. Salmeterol was significantly more effective than theophylline or placebo in improving mean morning PEF over the entire 12 weeks (P < or = .02). Mean predose FEV1 improved significantly with salmeterol compared with placebo (P < .001); there was no difference between theophylline and placebo. Salmeterol was also significantly more effective than theophylline or placebo (P < .02) in improving asthma symptoms, reducing nighttime awakenings, and reducing the daily use of albuterol. After 12 weeks of treatment, patients in the salmeterol group expressed significantly greater overall satisfaction with their asthma medication than did patients who received theophylline (P < .01). Patients in the theophylline group experienced more gastrointestinal adverse events than did patients in the salmeterol group (P < .05).
                Salmeterol, 42 mg twice daily, was better tolerated and significantly more effective than extended-release theophylline twice daily in the maintenance treatment of asthma. Recently there has been increased interest in the role of bronchodilators in the maintenance therapy of asthma in childhood. We report the use of slow-release aminophylline (Phyllocontin Continus tablets) in childhood asthma. Ten patients, all of whom were receiving disodium cromoglycate (DSG), were given a single dose of Phyllocontin tablets (12.5 mg/kg) and observed over a period of 8 hours. Measurements of peak flow rate (PFR) and forced expiratory volume in one second (FEV1) showed an increase of at least 30% at 3 to 5 hours and the improvement continued to 8 hours. No effect was noted on heart rate. Ten patients were assessed over a 4-week period on DSG then over two 4-week periods on Phyllocontin tablets and placebo on a double-blind crossover basis. The dosage of Phyllocontin tablets used was 12.5 mg/kg twice daily. Using twice daily PFR recordings there was no significant difference between the two periods on DSG and Phyllocontin tablets. The reduction in PFR during the period on placebo was significant, however, and more markedly so between the period of placebo and the period on Phyllocontin tablets. We conclude that Phyllocontin tablets in these patients compared favourably with DSG in the maintenance therapy of asthma in childhood. The results obtained after single dose administration also suggest that a proportion of children with asthma may benefit from combined treatment with DSG and regular bronchodilators. The inhaled corticosteroid, fluticasone propionate, was compared with the oral bronchodilator theophylline in the maintenance treatment of asthma.
                The objective of the present study was to compare the efficacy and safety of twice-daily inhaled fluticasone propionate, 50 micrograms, and fluticasone propionate, 100 micrograms, with that of theophylline in the maintenance treatment of mild-to-moderate asthma.
                In this randomized, double-blind, placebo-controlled, parallel-group study, 353 adult and adolescent patients with asthma inadequately controlled with inhaled beta-agonist therapy alone received fluticasone propionate, 50 micrograms, or fluticasone propionate, 100 micrograms, by metered-dose inhaler; theophylline capsules; or placebo twice daily for 12 weeks. Only inhaled albuterol was permitted as needed for acute symptoms.
                Both fluticasone propionate groups had a significantly greater probability of remaining in the study (ie, meeting asthma stability criteria) than did either the theophylline or placebo group (P < or = .008); 39% and 51% in the theophylline and placebo groups, respectively, were withdrawn due to lack of treatment efficacy compared with 14% and 21% in the fluticasone propionate, 50 micrograms, and fluticasone propionate, 100 micrograms, groups. Both fluticasone propionate groups experienced significantly greater improvement in FEV1 and PEF compared with patients in the theophylline or placebo group (P < or = .004). The incidence of potentially drug-related adverse events was significantly greater in the theophylline group (25%) than in the placebo group (11%) (P = .031), while there were no differences between placebo and fluticasone propionate, 50 micrograms, (18%) or fluticasone propionate 100 micrograms, (22%).
                Twice daily treatment with inhaled fluticasone propionate 50 micrograms or 100 micrograms was significantly more effective than theophylline in the treatment of mild-to-moderate asthma. A double blind crossover trial with active or placebo slow release theophylline (Slo-phyllin) in children with asthma aged up to 4 years is described. Although no difference in symptom scores was shown, other differences in favour of active treatment were noted. We conclude that this preparation is of benefit in the management of the wheezing preschool child. The value of symptom scores as an index of clinical improvement is discussed. Administration of theophylline to asthmatic children is frequently associated with an adverse influence on their behavior. The efficacy and behavioral effects of the administration of high-dose theophylline (T) and ketotifen (K) in various combinations were evaluated prospectively in a double-blind, placebo controlled study in 55 children with moderately severe perennial asthma. During a baseline period of 2 weeks, theophylline (serum level of 10-20 micrograms/ml) was administered to all the children. After this period the patients were randomly allocated into four comparable groups. The children were treated during a 12-week period with: T+K-Placebo (T group); T+K (T+K group); half-dose T+K (T/2 + K group); or placebo of both T and K (P group). During the 12-week treatment period, as compared to the baseline period, only the three groups of children who received active therapy (T+P, T+K, T/2 + K) showed a similar reduction in the number of days with asthmatic symptomatology, improvement of the total asthmatic symptoms score, and increased PEFR. The behavioral activity of the children (assessed by the Conner's rating scale) improved significantly only in the groups receiving placebo or T/2 + K. The results of this study suggest that a combination therapy of half the recommended therapeutic dose of theophylline with ketotifen can be clinically as effective as therapy with a full dose of theophylline, but with significantly less adverse behavioral effects. After one year of sustained-release theophylline (SRT) treatment, 19 children with severe perennial asthma participated in a 6-week, placebo-controlled, randomized, double-blind cross-over study. The severity of their asthma was evaluated before SRT-treatment (pre-period) and one year later, both during the theophylline period and the placebo period of the double-blind study. Compared with the pre-period, all observed parameters, except the number of extra bronchodilators required, were statistically significantly improved in the placebo period of the double-blind trial performed after one year. In addition, except for peak expiratory flow measured at home and the number of acute attacks, all parameters were significantly improved during the theophylline period when compared with placebo treatment. During this study, mean serum theophylline level was 13.3 mg/l (range 7.8-19.4 mg/l). The results show that theophylline remains efficient after one year's administration. The much better control of the children's asthma following one year of treatment emphasizes the need for regular re-evaluation of children receiving continuous prophylactic treatment. Twenty school children with chronic asthma who despite regular prophylactic therapy continued to have troublesome nocturnal wheeze or cough entered a double-blind cross-over study in which a once daily theophylline preparation was compared with placebo to assess control of these symptoms. Seventeen children completed both phases of the study. Significant improvement was noted in the day and night symptom scores, the morning dip index and daily peak flow readings with a significant reduction in rescue bronchodilator inhaler usage during the active treatment period. Satisfactory serum theophylline concentrations were obtained 11-12 h post dose in all children using a standard dose of 18 mg/kg per day at 2000 hours. Three children were withdrawn because of minor side-effects. The theophylline preparation studied in conjunction with other conventional anti-asthma therapy was thus effective in controlling nocturnal symptoms. nan 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) A double blind crossover comparison of slow-release theophylline, ketotifen and placebo was carried out in 18 young children with perennial asthma. Theophylline significantly reduced symptoms and increased the mean peak expiratory flow rate. Transient nausea and vomiting was commoner during theophylline treatment but did not usually necessitate discontinuance of therapy. Twenty asthmatic children who had daily wheezing requiring constant medication as outpatients were given oral metaproterenol or oral theophylline in a randomized double-blind crossover study. Each medication was given for four weeks, after the theophylline dosage necessary to give a therapeutic level was established. Pulmonary function parameters, daily peak-flow measurements and diary symptom scores were statistically comparable in most patients during these four-week intervals. Metaproterenol may be used in place of oral theophylline for at least a four-week interval with no decrease in effectiveness. Concern about side-effects of theophylline prompted us to investigate whether this drug could be eliminated from the multi-medication regimen of severe asthmatics. We studied patients with a demonstrated requirement for systemic steroids who were taking most other available anti-asthma medications in an attempt to reduce systemic steroids while maintaining clinical stability. Five in-patients, 12-15 years old, completed a double-blind, cross-over trial of theophylline vs placebo. All were stable for 4 weeks prior to the study with normal spirometry and mildly elevated lung volumes. Regular medications consisted of long-acting theophylline with levels between 12 mcg/ml and 16 mcg/ml, and prednisone 10-30 mg on alternate days. In addition, they were all taking inhaled metaproterenol, cromolyn sodium, atropine sulphate, and beclomethasone dipropionate four times daily (qid). Patients received either theophylline or placebo during two drug periods. All other medications were unchanged. Parameters measured were symptom score, number of extra respiratory treatments (prn RTs), increase in steroid dosage, and daily spirometry. During the placebo period, all five patients required increased steroids, daily spirometry decreased and three patients developed severe exacerbations unrelated to viral infection. A marked increase in symptom score occurred within 48 hr of discontinuing theophylline in all. These findings emphasize that theophylline is beneficial in a subset of severe asthmatics who cannot be controlled with all other available bronchodilators, cromolyn, and inhaled and systemic steroids.
Xanthines as first-line preventer alleviate symptoms and reduce requirement for rescue medication in children with mild to moderate asthma. When compared with ICS they were less effective in preventing exacerbations. Xanthines had similar efficacy as single preventative agent compared with regular SABA and SCG. Evidence on AEs (adverse effects) was equivocal: there was evidence for increased AEs overall, but no evidence that any specific AE (including effects on behaviour and attention) occurred more frequently than with placebo. There is insufficient evidence from available studies to make firm conclusions about the effectiveness of xanthines as add-on preventative treatment to ICS, and there are no published paediatric studies comparing xanthines with alternatives in this role. Our data suggest that xanthines are only suitable as first-line preventative asthma therapy in children when ICS are not available. Pre-trial exposure to the agents assessed may have pre-disposed the trial populations to tolerate the drug, and may have threatened blinding. They may have a role as add-on therapy in more severe asthma not controlled by ICS, but further studies are needed to examine this, and to define the risk-benefit ratio compared with other agents.