A comparative trial of choline theophyllinate and controlled release aminophylline in chronic childhood asthma

A comparison of pharmacokinetics and therapeutic effects of a standard oral theophylline preparation (Choline Theophyllinate) and controlled release aminophylline (Phyllocontin) was made in two parallel double blind trials in 25 children with chronic asthma. Fourteen children entered a double blind cross-over trial; the remaining 11 were allocated to a parallel trial with no change of theophylline preparation throughout. Sustained plasma theophylline levels were observed with the controlled release preparation in contrast to the low morning levels obtained with Choline Theophyllinate. No significant differences were found for peak theophylline levels, morning or evening peak flow rates or required access to other bronchodilators. However nocturnal symptoms were significantly reduced and daytime activity scores improved (P less than 0.05) on the controlled release preparation. The sustained plasma theophylline levels found in children taking the controlled release aminophylline may have provided a small but useful therapeutic advantage over the standard preparation.     

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     

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.     

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     

Clinical and bronchodilating efficacy of controlled-release theophylline as a function of its serum concentrations in preschool children

To evaluate the dose-effect relationship of a controlled-release theophylline in preschool children, 20 patients with asthma (mean age 4.8 years, range 2 1/2 to 7 years) were given three different dose levels (13.4 +/- 1.4, 18.4 +/- 1.6, and 23.5 +/- 2.0 mg/kg/day, mean +/- SD) at 12-hour intervals for 2 weeks. Subjective variables, peak expiratory flow rate, and co-medications were recorded daily; clinical condition, serum theophylline levels, and lung function measured with a multiple forced oscillation technique were assessed at the end of each period. The morning predose (through) and 4-hour postdose (peak) serum theophylline concentrations increased in an approximately linear fashion with increasing dose. In the majority of patients, dose levels of 20 to 25 mg/kg/day maintained serum concentrations within a clinically effective range, with an acceptable level of fluctuation. However, wide interindividual variations in serum theophylline concentrations were observed, indicating that for optimal treatment individualization of dosage is preferable. Efficacy was related to serum concentration and, less closely, to the dose administered. Symptom scores for night cough, wheeze, and activity showed small improvements between 5 and 10 mg X 1(-1) and marked improvements above 10 mg X 1(-1), whereas lung function values improved in a linear fashion across the serum concentration range. The serum theophylline concentration-response curves varied in an approximately parallel manner between individuals.     

Efficacy of salmeterol in the treatment of childhood asthma

The aim of the clinical study reported here was to investigate the efficacy of salmeterol, a new long-acting selective β2-agonist, in patients with bronchial asthma. Twenty-four children with moderate asthma were enrolled in the longitudinal study, consisting of a run-in period of 2 weeks followed by a treatment period of 4 weeks. Maintenance treatment consisted of inhaled corticosteroid and disodium cromoglycate, or both, at the same daily dose throughout the study. During the run-in period, the patients continued to inhale salbutamol when needed and some of them (37%) also received theophylline. They were subsequently treated with salmeterol 50 μg twice daily and prn salbutamol for 4 weeks. Efficacy was evaluated using symptom scores and pulmonary function tests including forced vital capacity parameters, pulmonary volumes, airway resistance and specific airway conductance that were measured sensitively by a whole body plethysmograph. As a result, salmeterol produced significant improvement in morning and evening peak expiratory flow rates, vital capacity, airway resistance, conductance and asthma symptoms versus salbutamol and theophylline. Adverse reactions were judged to be mild and few.     

EVALUATION OF A NEW SUSTAINED-RELEASE THEOPHYLLINE TABLET FOR CHILDREN

Abstract. Selvig, K., Alme, A., Rugs tad, H. E., Aas, K. and Bjerve, K. S. (Institute of Clinical Biochemistry, the Allergy Institute Voksentoppen, Department of Paediatrics and Department of Clinical Pharmacology, Rikshospitalet, Oslo 1, Norway). Evaluation of a new sustained-release theophylline tablet for children. Acta Paediatr Scand, 70: 929, 1981.-A new, low dose sustained-release tablet of theophylline has been developed in order to facilitate a correct dose regimen in asthmatic children treated with theophylline. The formulation (Euphyllin® retard mite w/groove) contains 128 mg of theophylline, and can easily be divided. The extent of bioavailability in adults is 0.91, and the peak serum concentration is reached after 8.7 h. 25 children treated with plain theophylline tablets were followed when changing to the sustained-release tablets. Compared to the plain tablets, the serum theophylline concentration before the morning dose was 29 μmol/l higher (range 12–51) when the same daily dose was given as a sustained-release preparation. The serum concentration fluctuations during one dosing interval were reduced with 13 μmol/l (0–26). Mild gastrointestinal side effects reported by the children when using the plain theophylline tablets all disappeared on changing to the sustained-release tablets.     

Bioavailability of a slow-release theophylline capsule given twice daily to preschool children with chronic asthma: comparison with liquid theophylline

The reliability of slow-release theophylline products in young children has been questioned. Therefore, we studied the bioavailability of a commonly prescribed slow-release theophylline formulation (Slo-Bid Gyrocaps), administered twice daily by sprinkling the beads on applesauce. Serial measurements of serum theophylline concentrations were obtained during steady state in eight children (ages 1.6 to 5 years) after receiving a reference liquid theophylline product every six hours and also while receiving the slow-release product every 12 hours. The morning dose of slow-release theophylline was given before the child had eaten, and the evening dose was given two hours after supper. The extent of absorption of the slow-release product was 98.3 +/- 20.2% (mean +/- SD) relative to the liquid reference. The serum concentration fluctuations, expressed as percentage of the measured trough, did not differ between the two products: 108 +/- 59% v 129 +/- 97% (P greater than .05) for reference and slow-release products, respectively. Three of the eight patients had unacceptably large fluctuations (greater than 100%) while receiving the slow-release regimen, and two of these three had unacceptable fluctuations while receiving the liquid reference. The rate of absorption was slower after the evening dose of slow-release product (postprandial), resulting in significantly smaller fluctuations, and lower peak concentrations. Time to peak concentration while receiving the slow-release regimen varied from two to four hours after the evening dose and from two to eight hours after the morning dose. However, the average difference between the peak concentration and the four-hour measurement after the morning dose was only 0.3 microgram/mL (range 0 to 2.6 micrograms/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma

The single- and multiple-dose absorption characteristics of a new sustained-release theophylline preparation, which has been formulated for once per day dosing in adults, were investigated in children aged 8 to 14 years. Four single doses were studied, each dose separated by 1 week. During steady state the preparation was given once daily in the morning for 1 week, and serum theophylline concentration was determined through two dosing intervals (48 hours). The product showed excellent sustained-release characteristics and consistent absorption profiles, which were not affected to any clinically important extent by the intake of various meals. After single doses, only 77% to 91% of the product was absorbed during the first 28 hours after dosing. However, bioavailability was complete both after single doses and during steady state. Eight of 14 children had steady-state fluctuations in serum theophylline levels of less than 90% when given doses once daily. Steady-state day-to-day variations in serum theophylline profiles were small in all patients except one, in whom differences up to 33 mumol/L (6 micrograms/mL) were seen (8 hours after dosing). We conclude that this formulation is completely absorbed at a sufficiently slow and consistent rate to permit acceptable fluctuations in absorption with once daily dosing for many, but not all, patients. However, it should not be used in very young children until bioavailability has been studied in this age group.     

Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma.

We aimed to compare the efficacy and safety of budesonide/formoterol (Symbicort) with budesonide alone (Pulmicort) or budesonide (Pulmicort) and formoterol (Oxis) administered via separate inhalers in children with asthma. In a 12 wk, double-blind study, a total of 630 children with asthma (mean age 8 yr [4-11 yr]; mean forced expiratory volume in 1 s (FEV(1)) 92% predicted; mean inhaled corticosteroid dose 454 microg/day) were randomized to: budesonide/formoterol (80/4.5 microg, two inhalations twice daily); a corresponding dose of budesonide alone (100 microg, two inhalations twice daily); or a corresponding dose of budesonide (100 microg, two inhalations twice daily) and formoterol (4.5 microg, two inhalations twice daily) (budesonide + formoterol in separate inhalers). The primary efficacy variable was the change from baseline to treatment (average of the 12-wk treatment period) in morning peak expiratory flow (PEF). Other changes in lung function and asthma symptoms were assessed, as was safety. Budesonide/formoterol significantly improved morning PEF, evening PEF and FEV(1) compared with budesonide (all p < 0.001); there was no significant difference between budesonide/formoterol and budesonide + formoterol in separate inhalers for these variables. All other diary card variables improved from baseline in all treatment groups; there were no significant between-group differences. Adverse-event profiles were similar in all groups; there were no serious asthma-related adverse events in any treatment group. Conclusion: budesonide/formoterol significantly improved lung function in children (aged 4-11 yr) with asthma compared with budesonide alone. Budesonide/formoterol is a safe and effective treatment option for children with asthma.     

Fluticasone propionate in asthma: a long term dose comparison study.

BACKGROUND: Few dose ranging studies have investigated optimal dosing with inhaled corticosteroids in children with asthma. AIMS: To compare the efficacy and tolerability of fluticasone propionate 100 or 200 microg twice daily in children with moderate to severe asthma for one year. METHODS: One year, randomised, double blind, parallel group, multicentre study. Children aged 4-11 years (n = 528) with moderate to severe asthma who had previously received high dose inhaled corticosteroids were given fluticasone propionate 100 or 200 microg twice daily for the 52 week treatment period. Efficacy (exacerbations, lung function, and symptoms) and tolerability (adverse events and cortisol levels) were measured. RESULTS: There was a non-significant decreased risk of experiencing an exacerbation at any time with fluticasone propionate 200 microg twice daily compared with fluticasone propionate 100 microg twice daily. This difference reached significance among patients with more severe asthma (defined by previous inhaled corticosteroid dose >800 microg/day). Daily record card morning peak expiratory flow (PEF) in the total population improved significantly more with the higher dose of fluticasone propionate (between group difference, weeks 1-52: 11.4 l/min). Clinic visit mean PEF improved from baseline with both doses, but the response was significantly greater with the higher dose (between group difference, week 52: 17.8 l/min). Both doses were equally well tolerated and overnight urinary cortisol concentrations were unchanged or slightly increased during treatment with either dose. CONCLUSION: This long term dose comparison study shows that treatment with fluticasone propionate 200 micro g twice daily may offer benefits over a lower dose, particularly in children with more severe asthma.     

Once a day theophylline; serum concentrations.

Twenty four hour profiles of serum theophylline concentrations were examined in 15 asthmatic children taking a new theophylline preparation once a day. Peak concentrations occurred at a time when nocturnal wheezing is likely. Fluctuation in concentrations throughout the day was greater than with other currently available preparations, but the importance of this has yet to be determined.     

The effect of reduction of maintenance treatment on circadian variation in peak expiratory flow rate values in asthmatic children

We investigated in well controlled asthmatic children whether it is possible to predict by measuring daytime forced expiratory volume in one second, the decline in nocturnal peak expiratory flow rate values after withdrawal of maintenance medication. Forced expiratory volume in one second and peak expiratory flow rate were measured in the outpatient clinic, on the last day with medication. Peak expiratory flow rates were then measured every four hours on days 4, 5 and 6 without medication. Seventeen children showed an amplitude in circadian peak expiratory flow rate values of more than 20% (group I) and nine children showed an amplitude of 20% or less on the three study days (group II). Mean values +/- SEM were 34.7 +/- 2.1% and 10.5 +/- 1.5%, respectively. Forced expiratory volume in one second values were comparable in both groups. Daytime peak expiratory flow rate values before and after withdrawal, remained on the same level in both groups. In group I peak expiratory flow rate values of 24.00 and 08.00 hours on day 6 were significantly lower (p less than 0.05) than on day 4. The results indicate that history and daytime pulmonary function measurements alone, are insufficient to assess the clinical situation and suggest that a decrease in early morning peak expiratory flow rate value (08.00 hours) is an early sign of deterioration of the disease state, after reduction of medication.     

The Effect of Reduction of Maintenance Treatment on Circadian Variation in Peak Expiratory Flow Rate Values in Asthmatic Children

ABSTRACT. We investigated in well controlled asthmatic children whether it is possible to predict by measuring daytime forced expiratory volume in one second, the decline in nocturnal peak expiratory flow rate values after withdrawal of maintenance medication. Forced expiratory volume in one second and peak expiratory flow rate were measured in the outpatient clinic, on the last day with medication. Peak expiratory flow rates were then measured every four hours on days 4, 5 and 6 without medication. Seventeen children showed an amplitude in circadian peak expiratory flow rate values of more than 20% (group I) and nine children showed an amplitude of 20% or less on the three study days (group II). Mean values ± SEM were 34.7±2.1% and 10.5±1.5%, respectively. Forced expiratory volume in one second values were comparable in both groups. Daytime peak expiratory flow rate values before and after withdrawal, remained on the same level in both groups. In group I peak expiratory flow rate values of 24.00 and 08.00 hours on day 6 were significantly lower ( p <0.05) than on day 4. The results indicate that history and daytime pulmonary function measurements alone, are insufficient to assess the clinical situation and suggest that a decrease in early morning peak expiratory flow rate value (08.00 hours) is an early sign of deterioration of the disease state, after reduction of medication.     

Fluticasone propionate in asthma: a long term dose comparison study

Background: Few dose ranging studies have investigated optimal dosing with inhaled corticosteroids in children with asthma. Aims: To compare the efficacy and tolerability of fluticasone propionate 100 or 200 µg twice daily in children with moderate to severe asthma for one year. Methods: One year, randomised, double blind, parallel group, multicentre study. Children aged 4–11 years (n = 528) with moderate to severe asthma who had previously received high dose inhaled corticosteroids were given fluticasone propionate 100 or 200 µg twice daily for the 52 week treatment period. Efficacy (exacerbations, lung function, and symptoms) and tolerability (adverse events and cortisol levels) were measured. Results: There was a non-significant decreased risk of experiencing an exacerbation at any time with fluticasone propionate 200 µg twice daily compared with fluticasone propionate 100 µg twice daily. This difference reached significance among patients with more severe asthma (defined by previous inhaled corticosteroid dose >800 µg/day). Daily record card morning peak expiratory flow (PEF) in the total population improved significantly more with the higher dose of fluticasone propionate (between group difference, weeks 1–52: 11.4 l/min). Clinic visit mean PEF improved from baseline with both doses, but the response was significantly greater with the higher dose (between group difference, week 52: 17.8 l/min). Both doses were equally well tolerated and overnight urinary cortisol concentrations were unchanged or slightly increased during treatment with either dose. Conclusion: This long term dose comparison study shows that treatment with fluticasone propionate 200 µg twice daily may offer benefits over a lower dose, particularly in children with more severe asthma.     

Sustained-release terbutaline vs sustained-release theophylline in young patients with asthma

Twenty patients with asthma (mean age, 10.9 +/- 2 years) entered a six-week, randomized, double-blind, crossover comparison of sustained-release (S-R) terbutaline sulfate (Bricanyl Durules) vs S-R theophylline (Theo-Dur). In each two-week study period each patient received S-R theophylline twice daily in doses previously adjusted to give serum theophylline concentrations in the range of 10 to 20 mg/L (56 to 111 mumol/L); or S-R terbutaline sulfate, 5 mg twice daily; or S-R terbutaline sulfate, 7.5 mg twice daily. All treatment regimens produced significant improvement in one or more pulmonary function test values compared with prestudy values. The incidence of acute asthma episodes were similar during each treatment regimen. No clinically significant difference occurred between the regimens for daily symptom scores, peak expiratory flow rates, or use of a terbutaline metered-dose inhaler. At the end of the theophylline treatment period, the mean (+/- SD) theophylline level 12 to 14 hours after the last dose was 10.1 +/- 3.3 mg/L (56 +/- 18 mumol/L); at the end of the terbutaline treatment periods, the mean trough terbutaline levels were 2.22 micrograms/L (9.9 +/- 4.4 nmol/L) (S-R terbutaline sulfate, 5 mg twice daily) and 3.07 micrograms/L (13.7 +/- 5.4 nmol/L) (S-R terbutaline sulfate, 7.5 mg twice daily). Adverse effects, including tremor, occurred with similar frequency during all three drug regimens. Sustained-release formulations of theophylline and terbutaline, in the dosages studied, provided comparable control of asthma symptoms.     

The effectiveness of the short- and long-term use of crystallized theophylline in asthmatic children.

The bioavailability, duration of action, and efficacy of a crystallized tablet form of theophylline were studied in 16 nonsteroid-dependent asthmatic children. All required bronchodilator drugs daily for control of symptoms. Theophylline 125 mg, ephedrine SO4 30 mg, T + E, or placebo were given in a randomized, double-blind, crossover design on four separate days. Pulmonary function tests (FVC, FEV1, FEF25-75) and serum T levels were determined at 0, 4, 1, 2, 4, and 6 hours on both day one and after day 7 of a every-six-hour drug dosage schedule. Mean maximum T levels were achieved at two hours with a peak mean of 2.94 microgram/ml +/- 0.24 SEM on day one. On day 8, the maximum T levels were higher, with a peak mean at two hours of 4.69 microgram/ml +/- 0.49 SEM. Computer analyses for pharmokinetics are compatible with 100% absorption of this preparation. Pulmonary function tests were significantly improved (FEV1 20% and FEF25-75 15%) at T levels of 2 to 5 microgram/ml. Addition of E to the T regimen further improved pulmonary function only on day one and had no effect on the last study day.     

Diurnal rhythm in serum leptin

AIM: To assess 24-hour serum leptin levels in children. SUBJECTS AND METHODS: Five girls and two boys aged 10.4-13.6 (mean 12.2) years with pubertal stages I to III were studied. All children were healthy. A fasting blood sample was drawn at 08.00 hours, and thereafter samples were obtained every 2 hours throughout 24 hours until 08.00 hours the next morning. Serum leptin was measured by a specific radioimmunoassay. RESULTS: A statistically significant circadian variation was found in mean leptin profile expressed as a percentage of overall day mean (F-ratio =10.4; P<0.001) with trough and peak levels (+/- SEM) at 10.00 (6.55+/-1.52 mg/l) and 24.00 hours (10.99+/-2.34 mg/l), respectively. CONCLUSIONS: In normal children serum leptin levels exhibit a nocturnal increase and a decrease during the morning. The nocturnal rise may represent a time lagged stimulating effect of insulin. The diurnal rhythm needs to be considered when serum leptin is assessed in clinical studies.     

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目的观察布地耐德(BUD)联用福莫特罗(FOM)与单用双倍剂量BUD干粉吸入疗法对轻度持续性哮喘患儿的有效性和安全性,探讨儿童轻度持续性哮喘的理想治疗方案。方法选取2005-01—2005-06在广州医学院附属第一医院呼研所专科门诊就诊的轻度持续哮喘患儿50例,采取开放、随机、平行对照方法把50例患儿分为两组,分别吸入BUD联用FOM(B+F组)或双倍剂量BUD(Double B组)8周,药物均用都保干粉吸入装置吸入。8周的观察期内由患儿或家长记录哮喘日记,包括日间和夜间症状评分、无症状天数、其它平喘药物(包括应急用速效β2-受体激动剂、长效缓释茶碱、口服长效β2-受体激动剂、全身用糖皮质激素)使用情况,同时以简易峰流速仪监测其呼气峰流速值(PEF)作为主要肺功能指标。结果B+F组和Double B组在治疗8周后,日间症状及PEF均较治疗前明显改善,无症状天数明显增加,差异具有统计学意义(均P<0.05);与治疗前比较,B+F组在治疗8周后夜间症状评分明显下降(P<0.05),而Double B组治疗前后比较差异无统计学意义(P>0.05);两组间日间症状评分、夜间症状评分、无症状天数及PEF治疗前及治疗后比较差异均无统计学意义(均P>0.05)。两组间病情反复发作次数、需联合应用速效β2-受体激动剂次数及口服强的松、长效缓释茶碱或口服长效β2-受体激动剂的天数均无统计学意义(均P>0.05)。结论低剂量吸入糖皮质激素(ICS)联用长效β2-受体激动剂(LABA)与单用双倍剂量ICS治疗儿童轻度持续性哮喘的疗效相当。但从减少或避免ICS潜在的全身性副反应方面考虑,联用低剂量ICS+LABA可能是更好的选择。     

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.