Once a day theophylline in chronic childhood asthma?

The therapeutic effects of either morning or evening administration of a once-daily controlled release theophylline preparation (Uniphyllin) were studied in 17 asthmatic children. Neither morning nor evening administration produced therapeutic plasma theophylline levels throughout 24 h. Similarly, bronchodilation was not maintained during the same period. However, morning peak expiratory flow rates were significantly improved following evening dosage, suggesting a role for evening administration when nocturnal symptoms predominate.Abbreviations CR controlled release - PEFR peak expiratory flow rates     

Serum concentrations of theophylline in children following the administration of doses generally recommended: new dosage regimen required.

Serum concentrations of theophylline following intravenous and oral administration of aminophylline were studied in asthmatic children, 2--17 years of age. The biological half-life (t 1/2 beta) of theophylline varied between 165 and 495 min. The results revealed that an intravenous loading dose of 6 mg of aminophylline per kg body weight was necessary in order to obtain therapeutic concentrations in children who had not received the drug for the last 6 to 8 hours. The maintenance dose should be determined and controlled by use of serum concentration determinations. In a group of children receiving 5 mg of aminophylline per kg body weight 3 times a day orally, none had concentrations within the therapeutic range in the morning, and only 39% reached therapeutic levels 2 h after the morning dose. No correlation was found between the serum concentration of theophylline and the amount of drug given per kg body weight. The results show that theophylline concentration analysis is necessary to obtain adequate therapeutic levels in children without risking toxic effects.     

SERUM CONCENTRATIONS OF THEOPHYLLINE IN CHILDREN FOLLOWING THE ADMINISTRATION OF DOSES GENERALLY RECOMMENDED:NEW DOSAGE REGIMEN REQUIRED

Abstract. Serum concentrations of theophylline following intravenous and oral administration of aminophylline were studied in asthmatic children, 2–17 years of age. The biological half-life (β) of theophylline varied between 165 and 495 min. The results revealed that an intravenous loading dose of 6 mg of aminophylline per kg body weight was necessary in order to obtain therapeutic concentrations in children who had not received the drug for the last 6 to 8 hours. The maintenance dose should be determined and controlled by use of serum concentration determinations. In a group of children receiving 5 mg of aminophylline per kg body weight 3 times a day orally, none had concentrations within the therapeutic range in the morning, and only 39% reached therapeutic levels 2 h after the morning dose. No correlation was found between the serum concentration of theophylline and the amount of drug given per kg body weight. The results show that theophylline concentration analysis is necessary to obtain adequate therapeutic levels in children without risking toxic effects.     

A once daily theophylline preparation in prevention of nocturnal symptoms in childhood asthma

Twenty school children with chronic asthma who despite regular prophylactic therapy continued to have trouble-some 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.Abbreviations MDI morning dip index - SRT slow release theophylline - SCG disodium cromoglycate - PFR peak flow rate     

Slow release theophylline in preschool asthmatics.

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.     

Sustained release theophylline in nocturnal asthma.

Twice daily sustained release theophylline gave satisfactory steady serum theophylline concentrations in asthmatic children aged 7 to 14 years. The children showed improvement in symptoms, less frequent waking at night, reduced use of beta agonist inhalers, and improved early morning peak flows while being treated with this preparation. There was no improvement in peak flow at other times, but the patients recorded increased use of beta agonists during the placebo period.     

Randomised controlled trial of aminophylline for severe acute asthma.

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: Randomised, 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 enrollment 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.     

Effects of oral theophylline and oral salbutamol in the treatment of asthma.

A double-blind randomised controlled trial was conducted to study the effects of oral theophylline alone compared with oral theophylline and salbutamol in a sample of asthmatic children. Each treatment was administered at maximum recommended dosage. Children treated with the theophylline and salbutamol combination had higher pulse rates, lower peak flow measurements, and depressed blood theophylline levels. These results suggest that when given at maximum oral dosage, theophylline and salbutamol in combination, tend to interact negatively producing tachycardia and reduced therapeutic function.     

酮替芬对哮喘患儿茶碱药代动力学影响的研究

目的研究酮替芬对哮喘患儿茶碱药代动力学的影响。方法应用高效液相色谱仪测定茶碱血浓度,对１２例哮喘患儿单用氨茶碱和氨茶碱加酮替芬后两组茶碱药代动力学参数及浓度进行对照观察。结果加用酮替芬后,血清茶碱最高浓度降低２０１％,清除速率常数和清除率分别增加２４１％和５３７％,曲线下面积减少３２９％,清除半衰期缩短２４９％。结论酮替芬、氨茶碱相互作用可能增强茶碱治疗哮喘的安全性和有效性     

Theophylline pharmacokinetics in children,comparing sustained release spheres (Theo-Dur sprinkle) with elixir

A new sustained release theophylline preparation (Theo-Dur Sprinkle, TDS) was given b.i.d. and a theophylline elixir t.i.d. to eight children with bronchial asthma, 4–10 years of age, in an open study with a randomized cross over design. The serum concentration curves of theophylline were compared. The individual theophylline dose was close to 20 mg/kg body weight per day. On day 3 of each regimen, blood samples were taken 11 times over 24h. There were great differences between morning concentrations of theophylline, with a range from 0.9–10.7 mg/l in children given elixir, while corresponding values for children given TDS were 4.1–19.3 mg/l. Fluctuation during a dosing interval was 276% for elixir but only 54% in the case of TDS. The morning theophylline levels on two consecutive days did not differ significantly when the children were treated with TDS. The bioavailability of theophylline from TDS was 94% (range 54%–121%). Parents prefered TDS in seven of the eight cases. TDS showed satisfactory sustained release properties but the study confirmed the need for individually tailored dosage of theophylline based on monitoring of symptoms and serum concentrations.Abbreviations TDS Theo-Dur sprinkle - HPLC a liquid chromatographic method - AUC area under concentration curve - C_max maximum-theophylline concentration - C_min minimum theophylline concentration Subsidiary of AB Astra, Sweden     

Effect of controlled release salbutamol on nocturnal cough in asthma.

Sixteen asthmatic children completed a double blind placebo controlled crossover study of controlled release salbutamol (CRS) to assess its efficacy in controlling night time cough. Children with asthma were enrolled into the study on the basis of a history of persistent cough confirmed by two overnight tape recordings at home. Outcome was measured by two overnight tapes on each medication. Other treatment was unaffected. There was no significant fall in cough counts on CRS. Median scores were 14.5 and 12.0 coughing episodes per night for CRS and placebo respectively. Mean overnight oxygen saturation was identical in both treatment periods but morning peak flow showed a trend towards improvement on CRS. Treatment with CRS does not have a significant effect in control of night cough although it may improve objective measurements of lung function.     

Behavior abnormalities and poor school performance due to oral theophylline use

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.     

Aminophylline therapy in children: guidelines for dosage

The oral dosage of aminophylline required for therapeutic "trough" serum theophylline levels was studied in 150 children, 16 months to 19 years old (mean 8.28 years). Dosage requirements tended to be higher for children under 10 years, but marked person-to-person variability in the relation of dose to serum level was seen at all ages. Individual patients generally maintained consistent serum levels when receiving unchanging doses, although intercurrent disease sometimes disrupted this relationship. Individualization of oral dosage based on frequent serum measurements is necessary to maintain theophylline levels in the therapeutic range and to avoid toxicity.     

Intraindividual changes in theophylline clearance during constant aminophylline infusion in children with acute asthma

Intraindividual changes in theophylline clearance were examined in 13 children with acute exacerbation of asthma receiving a 72-hour constant intravenous infusion of aminophylline. The mean (+/- SD) first, second, and third clearances measured at 24, 48, and 72 hours after the infusion increased from 58.1 +/- 13.8 to 69.7 +/- 28.0 to 84.1 +/- 36.3 ml/hr/kg, respectively (P less than 0.02 from the first and P less than 0.05 from the second). Our results suggest that substantial intraindividual changes in theophylline clearance can occur over a rather short time during intravenously administered aminophylline therapy for acute asthma in children. We recommend that plasma theophylline concentrations be monitored frequently and that aminophylline infusion rate be adjusted on the basis of the measured theophylline concentration data during an acute episode of asthma in the pediatric patient.     

Effect of formoterol on clinical parameters and lung functions in patients with bronchial asthma: a randomised controlled trial.

AIMS: To determine the role of formoterol in the treatment of children with bronchial asthma who are symptomatic despite regular use of inhaled corticosteroids. METHODS: A randomised, double blind, parallel group, placebo controlled study to investigate the effects of inhaled formoterol (12 microg twice a day) in 32 children with moderate to severe bronchial asthma. The study consisted of two week run in periods and six week treatment periods, during both of which the patients continued their regular anti-inflammatory drugs. The efficacy parameters were symptom scores, bronchodilator use, daily peak expiratory flow rates (PEFR), methacholine hyper-reactivity, forced expiratory volume in one second (FEV1), lung volumes, and airway conductance. RESULTS: Formoterol treatment for six weeks decreased symptom scores, PEFR variability, and the number of rescue salbutamol doses, and increased morning and evening PEFR significantly. No adverse reactions were seen. CONCLUSION: These findings suggest that inhaled formoterol is effective in controlling chronic asthma symptoms in children who are symptomatic despite regular use of inhaled corticosteroids.     

Monitoring long-term therapy with theophylline preparations in children with asthma

In 78 children (4 to 17 years of age) with moderate or severe asthma who were additionally treated with sustained-release theophylline preparations, different ways of drug monitoring were examined. Analysis of plasma and saliva theophylline was performed by means of high performance liquid chromatography. Saliva theophylline turned out to permit a reliable prediction of plasma theophylline, if an individual regression is calculated for each patient, basing on 3 simultaneously performed measurements of theophylline levels in saliva and plasma within the therapeutic range of 8 to 20 mg/l. In 25 patients theophylline levels were determined in venous and capillary blood. There was an excellent agreement (r = 0.97). Thus, a convenient monitoring of theophylline treatment in children is possible.     

Prediction of intravenous theophylline dosage based on a single, nonsteady-state concentration: a clinical study of childhood status asthmaticus

A pharmacokinetic model was applied to achieve therapeutic serum theophylline concentrations rapidly in 25 children with status asthmaticus. A sustained release theophylline preparation had been taken within 36 hours by 12 children; within 14 hours, seven had taken an immediate release preparation; for six children, no theophylline was taken before hospital admission. Single serum theophylline concentrations were determined at nonsteady-state conditions within 13.5 hours of admission (median 6.75 hours). An iterative program was applied to predict the steady-state theophylline concentration as well as necessary adjustments in dosage. Measured steady-state concentrations were then compared with the predicted values. The median measured steady-state concentration was 15 mg/L, and the median predicted steady-state level was 13 mg/L. The least squares regression line was: Measured = 0.738 predicted + 4.77; r = .721, P less than .01. No patient experienced symptoms of toxicity. This technique affords the possibility of accurate prediction of steady-state theophylline concentrations and dosing requirements with a minimum number of serum concentration determinations in children with status asthmaticus.     

Pharmacokinetic analysis of the disposition of intravenous theophylline in young children.

The disposition of a single intravenous dose of theophylline, 3.2 mg/kg, was studied using a high-pressure liquid chromatographic assay in ten asthmatic children one to four years of age. The man plasma theophylline clearance was 0.100 +/- 0.036 l/kg/hr, kel 0.49 +/- 0.30 hr-1, betat1/2 3.38 +/- 1.11 hr, alphat1/2 0.13 +/- 0.09 hr, and V1 0.25 +/- 0.13 1/kg. Plasma theophylline clearance was approximately 40% greater in these children than that reported in adults, mainly due to an increased rate of drug elimination. Large interindividual differences were observed. Analysis of data using either a two- or one-compartment model yielded almost identical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetic constants predict that a maintenance dose rate for aminophylline of 30 mg/kg/day, after a loading dose of 5.6 mg/kg, would rapidly achieve and maintain a mean steady-state plasma concentration of theophylline of 10 mg/1. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement of steady state) have not yet been conducted.     

Inconsistent absorption from a sustained-release theophylline preparation during continuous therapy in asthmatic children

During routine monitoring of hospitalized children with asthma receiving a sustained-release theophylline formulation, we frequently observe unpredictable fluctuations in serum theophylline concentration (STC). We evaluated eight asthmatic patients (ages 4 to 17 years) with inconsistent STCs to determine the cause of this phenomenon. Only minimal variation in STC and therefore theophylline clearance was noted during a 24-hour period of continuous intravenous aminophylline infusion. However, marked variability in STC was observed when measured every 2 hours for 48 hours after 6 days of continuous therapy orally. In addition, the time required to reach peak and trough STCs varied from dose to dose. Inasmuch as clearance was shown to be constant, the variability was attributed to inconsistent theophylline absorption. Unpredictable fluctuations of STC secondary to variable absorption from this sustained-release theophylline preparation may occur in certain patients. Appreciation of this potential variability is necessary for the proper interpretation of STC measurements and subsequent dosage adjustment.     

Systematic review of the dose-response relation of inhaled fluticasone propionate.

AIMS: To examine the dose-response relation of inhaled fluticasone for both efficacy and adrenal function in children with asthma. METHODS: Systematic review of double blind randomised dose-response studies of fluticasone in children of at least 4 weeks duration. MAIN OUTCOME MEASURES: FEV1, morning peak expiratory flow, night awakenings, beta agonist use, major exacerbations, 12 or 24 hour urinary cortisol, peak plasma cortisol post-stimulation. RESULTS: Seven studies of 1733 children with asthma met the inclusion criteria for efficacy. The dose-response curve for each efficacy outcome measure suggested that the response began to plateau between 100 and 200 microg per day with additional efficacy at the 400 microg per day dose shown in one study of severe asthmatics. Five studies of 1096 children with asthma met the inclusion criteria for assessment of adrenal function. The largest placebo controlled study of 437 children reported no difference in 24 hour urinary cortisol between placebo and fluticasone at doses of 100 and 200 microg per day. The non-placebo controlled study of 528 children reported significant suppression of overnight urinary cortisol levels with fluticasone at 400 compared with 200 microg per day. CONCLUSIONS: There is insufficient data to determine the dose-response of fluticasone in children at doses >400 microg per day. The dose-response curve for fluticasone appears to plateau between 100 and 200 microg per day for efficacy. There was additional efficacy at the 400 microg per day dose in children with severe asthma; however there was evidence of adrenal suppression at this dose.