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 Three children were withdrawn because of minor side-effects.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     

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)     

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 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.     

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.     

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.     

Sustained-release theophylline preparations in asthmatic children. A short-term comparison of two products and the relationship of serum theophylline levels and pulmonary function changes

In a four-week study, 20 children with chronic asthma were treated in a randomized, double-blind, crossover manner with two sustained-release theophylline preparations (Theo-Dur and Uniphyl) to compare their drug concentrations and clinical efficacy. In addition, the effects of serum theophylline concentration on results of pulmonary function tests (PFTs) were evaluated. Twelve-hour doses (to achieve serum concentrations between 10 and 20 mg/L) of each drug were given for two weeks. Diaries of asthma symptoms and peak flows were kept daily. After 14 days of each treatment, children returned for measurement of theophylline levels and PFTs over a 12-hour period. The two drugs were equally effective in clinically controlling asthma over the two weeks of treatment. Serum theophylline levels obtained over the 12-hour dosing periods were not significantly different. Uniphyl provided less (but not significantly) deviation between peak and trough levels. Analysis of individual patient data did not reveal a predictable relationship between serum theophylline concentrations and results of PFTs.     

Apparent inconsistent theophylline absorption from sustained release capsules

Sustained release theophylline products can improve compliance and symptom control in children with asthma. This study examines theophylline serum concentration monitoring in pediatric patients. Fifteen children with documented asthma were randomized to receive either Slo-bid Gyrocaps or Theo-dur Sprinkle for 1 month, and then crossed over to the other product. On the last day of each study period, theophylline serum concentrations were obtained prior to the morning dose and 4 hours later. In two patients receiving Theo-dur Sprinkle and six with Slo-bid Gyrocaps, the 4-hour serum concentration was lower than the pre-dose concentration. The change between the pre-dose and post-dose serum concentrations for Theo-dur Sprinkle ranged from a decrease of 2.8 mg/L to an increase of 4.9 mg/L, and, for Slo-bid Gyrocaps, from a decrease of 4.6 mg/L to an increase of 10.5 mg/L. The inconsistent theophylline absorption with each product makes dosage adjustment difficult.     

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.     

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     

Acute renal failure in children: prognostic features after treatment with acute dialysis

A 12-year review (1972–1983) is presented of 76 children who were dialysed because of acute renal failure. The causes of acute renal failure were mainly the haemolyticuraemic syndrome (53%), trauma (16%) and operation (13%).Fifty-eight children (76%) survived, 18 children (24%) died. Fifty-two children, the majority suffering from haemolytic-uraemic syndrome, regained complete or partial renal function after a period of dialysis lasting between 1 and 57 days. One to 7.7 years after dialysis, clearance studies with inulin (C_In), p-aminohippuric acid (C_PAH) and phosphate (T_p/C_In) for staging renal function were carried out. The results of this investigation show a significant inverse correlation between the glomerular function regained and the duration of intermittent dialysis.Abbreviations C_In clearance of inulin - C_PAH clearance of p-aminohippuric acid - FF filtration fraction - T_p/C_In fractional phosphate reabsorption - HUS haemolytic-uraemic syndrome - ARF acute renal failure - SCR serum creatinine - GFR glomerular filtration rate - CRF chronic renal failure - a.t. antihypertensive treatment     

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.     

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.     

Comparative effects of theophylline and caffeine on respiratory function of prematurely bora infants

The aim of this study was to determine the relative effects of theophylline and caffeine on neonatal respiratory function. Fifty-three preterm infants (45 infants with a median gestational age of 28 weeks, range 24–34 weeks completed the protocol) were randomized to receive either theophylline (loading dose 4 mg/kg followed by 4 mg/kg/day) or caffeine (loading dose 10 mg/kg followed by 5 mg/kg/day). Compliance of the respiratory system (C_RS), strength of Hering Breuer reflex and the inspired oxygen concentration requirement were measured immediately prior to, 24 h and 7 days after commencing therapy. There was no statistically significant difference in the patient characteristics of the two groups, but only the theophylline group contained immature infants (i.e. < 26 weeks gestational age (n = 7)). At 24 h, there was a significant improvement in C_RS and reduction in supplementary oxygen requirements in the caffeine group (p < 0.01), in the theophylline group no such significant effects were seen. In the study population overall, after 7 days of treatment in both the theophylline and caffeine groups there was an improvement in C_RS (p < 0.05 and p < 0.01 respectively) and a reduction in the inspired oxygen concentration (p < 0.05 and p < 0.01 respectively). There was, however, a significant reduction in the strength of the Hering Breuer reflex only in the caffeine group (p < 0.05) and this was a decrease which related to the change in C_RS (p < 0.05). The only statistically significant difference in the magnitude of change in C_RS, reflex strength or supplementary oxygen requirements between the two groups was that the reduction in inspired oxygen requirement in the caffeine group was greater man that in the theophylline treated infants at 24 h (p < 0.05). We conclude theophylline and caffeine have similar effects on neonatal respiratory function, but our results suggest caffeine administration may be associated with an earlier onset of action.     

Renal functional maturation: renal handling of proteins by mature and immature newborns

Renal clearance of creatinine (C_cr), total protein excterion, urinary protein composition and renal clearance of albumin (C_alb) were measured and calculated in male premature and mature infants of gestational age 29–41 weeks and in mature infants 1 and 3 months of age. Total protein excretion decreased slightly but not significantly during maturation. The urinary protein composition changed significantly as the fraction of low molecular weight proteins decreased from 38% at a gestational age of 29–33 weeks to 24% in mature infants aged 3 months, the albumin fraction increased from 39%–46% and the proportion of higher molecular weight proteins increased from 12%–29%, respectively. C_alb decreased from 2.73–0.80 l/min/1.73 m² in the presence of a rise in C_cr, resulting in a significant fall of the ratio C_alb/C_cr from 0.0137 in the youngest prematures to 0.00147 in 3-month-old mature infants.Abbreviations C_cr clearance of craatinine - C_alb clearance of albumin - GA gestational age - GFR glomerular filtration rate - HMW high molecular weight - LMW low molecular weight - A albumin     

Predicting concentrations in children presenting with acetaminophen overdose.

OBJECTIVE: To predict serum concentrations to evaluate and improve guidelines for the treatment of children (1 to 5 years) with accidental ingestion of acetaminophen elixir. METHODS: Acetaminophen concentrations for 1000 children were simulated with pharmacokinetic parameters and their expected variability. The distribution of concentrations arising from a 300 mg/kg dose at different age groups was predicted. These predictions were validated by comparison with concentrations obtained at 4 hours from 121 children with accidental ingestion of acetaminophen elixir. RESULTS: No child who presented with overdose had a concentration in the probable risk area of the Rumack-Matthew toxicity nomogram. Enteral charcoal administered 98 minutes (SD 44) after ingestion had no effect on serum concentrations. The simulation predicted that an acetaminophen dose of 300 mg/kg would result in concentrations of 32 to 208 mg/L (95% CI) at 4 hours after ingestion. The maximum concentration occurred before 2 hours in 95% of simulated children. CONCLUSION: Children (1 to 5 years) with reported ingestion of >250 mg/kg acetaminophen elixir should have serum concentrations measured at 2 hours after ingestion rather than at the 4-hour time point recommended in adults. This can be expected to speed discharge and reduce anxiety. The use of enteral charcoal is unlikely to enhance acetaminophen elimination, unless it is given within an hour of acetaminophen ingestion.     

Cimetidine pharmacokinetics and dosage requirements in children

The pharmacokinetics of cimetidine (10 mg/kg) were investigated in 11 children following an oral dose and in 9 children following an intravenous dose. The children ranged in age from 4–13 years and were undergoing radiology for upper gastrointestinal tract pain. Compared with a group of adults, the children had a higher total body clearance (11.6±3.4 versus 7.0±2.5 ml/min per kg; P<0.005), a larger apparent volume of distribution (1.24±0.40 versus 0.80±0.24 l/kg; P<0.005) and a shorter elimination half-life (83±26 versus 122±16 min; P<0.001) of cimetidine. Renal clearance in children comprised 70% of total body clearance, more than double that of adults (9.0±1.9 versus 4.2±2.1 ml/min per kg; P<0.001). The area under the cimetidine plasma concentration: time curve after the oral dose was on average 42% in children compared with adults. The mechanism for the increased elimination of cimetidine in children is suggested to be an increase in the renal tubular secretory transport of cimetidine in the kidney. A statistically significant negative correlatio was observed between age and cimetidine renal clearance. A cimetidine dosage regimen of approximately 30 mg/kg per day in three to four divided doses would be an appropriate dose in children.Abbreviations AUC area under the cimetidine blood concentration: time curve - V_ss volume of distribution - Cl_T total systemic clearance - Cl_r renal clearance - Cl_nr non-renal clearance     

Prevalence of abnormal urinary albumin excretion in adolescents and children with insulin dependent diabetes: the MIDAC study. Microalbinuria in Diabetic Adolescents and Children (MIDAC) research group

OBJECTIVE—To examine the prevalence of microalbuminuria, defined as an albumin to creatinine ratio (UAC) equal to or greater than 2mg/mmol in at least two of three early morning urine samples, in adolescents and children with insulin dependent diabetes mellitus.DESIGN—Centrally coordinated, cross sectional, multicentre study in paediatric diabetes outpatient clinics in the United Kingdom and Republic of Ireland.METHODS—Blood and urine samples collected between July 1997 and July 1998 were analysed at a central reference laboratory for HbA_1C using high performance liquid chromatography, and for urinary albumin and creatinine concentrations from which the UAC was derived (mg/mmol). Clinical data were collected locally and coordinated centrally.SUBJECTS—Patients, aged between 10 and 20 years, with insulin dependent diabetes mellitus for more than a year, attending diabetes outpatient clinics.RESULTS—A total of 1007 patients, comprising 69% of the eligible population of 1451, provided three early morning urine samples. Ninety eight (9.7%) had microalbuminuria using the currently accepted screening cut off of UAC ? 2 mg/mmol in at least two of three early morning urine samples. Significantly more girls than boys and significantly more pubertal and postpubertal patients had abnormal albumin excretion. Microalbuminuria was not associated with raised blood pressure.CONCLUSIONS—A prevalence of 9.7% for abnormal UAC was found in a cohort of 1007 children and adolescents aged 10-20 years. Thus a tenth of this national sample of young people were identified as being at particular risk of microvascular and later macrovascular disease.     

Rectal hydrocortisone during stress in patients with adrenal insufficiency

OBJECTIVE—Patients with glucocorticoid deficiency need lifelong glucocorticoid replacement treatment. During acute stressful events, steroid dosage must be increased several times, which is often problematical in children. This study investigated the reliability of rectal hydrocortisone administration as an alternative to the intramuscular route.
STUDY DESIGN—Serum cortisol was assessed during stress in normal children to determine the concentration that should be achieved after rectal hydrocortisone. Subsequently, serum cortisol concentrations were measured three hours after administering a suppository containing hydrocortisone 100 mg/m² to 57 patients with adrenocortical insufficiency. In eight patients, the time dependency of the cortisol rise after rectal administration was established.
RESULTS—In 51 previously healthy children admitted to hospital with an acute stressful condition, the mean serum cortisol concentration was 1092 nmol/l. Rectal hydrocortisone in patients with adrenocortical insufficiency resulted in a mean serum cortisol concentration of 1212 nmol/l three hours after insertion of the suppository containing hydrocortisone. In 14 of 57 children, serum cortisol was < 1000 nmol/l and in eight children it was below 600 nmol/l. One hour after administration, the mean cortisol concentration had reached 1000 nmol/l. This was sustained for more than four hours.
CONCLUSION—Rectal hydrocortisone is a safe alternative to parenteral administration in the self management of Addisonian prone conditions. However, because eight of 57 children did not achieve concentrations > 600 nmol/l, its use is recommended only after previously documenting an adequate serum cortisol concentration three hours after receiving a test dose.

     

Urinary excretion of calcium and magnesium in children

Urine calcium excretion in healthy children was 2·38±0·66 (SD; no. = 52) mg/kg per 24 hr and urinary magnesium excretion was 2·82±0·79 (SD; no. = 23). The 24-hour urine calcium excretion could be predicted with reasonable confidence from the calcium/creatinine concentration ratio of the second urine specimen passed in the morning. In this specimen the urine calcium/creatinine concentration ratio was 0·14±0·06 (SD; no. = 60) mg/mg and the magnesium/creatinine concentration ratio was 0·21±0·10 (SD; no. = 29) mg/mg.The upper limit of the urine calcium excretion is taken to be 4 mg/kg per 24 hr and that of the calcium/creatinine concentration ratio in the second morning urine is 0·25 mg/mg. After a milk load of 700 ml/1·73 m² the urinary calcium/creatinine concentration ratio rose in the first two hours, but in no sample exceeded 0·25 mg/mg.