Metabolism of theophylline to caffeine in premature newborn infants.

Plasma concentrations of theophylline and caffeine in seven premature neonates receiving theophylline orally for treatment of apnea at age one to 9 days were measured by high performance liquid chromatography, ultraviolet spectrophotometry, and mass spectrometry. Plasma concentrations of caffeine increased from 1.8 mg/l (range = 0.1 to 3.7) at day one to 3.7 mg/l (1.3 to 8.0) seven days after initiation of theophylline therapy. Similarly, plasma concentrations of theophylline were 4.6 mg/l (1.5 to 7.5) and 11.0 mg/l (4.0 to 19.0) on days one and 7 of theophylline therapy, respectively. In contrast, four normal adult volunteers given theophylline orally for eight to ten days had plasma theophylline concentrations ranging from 3 to 14 mg/l but no measurable caffeine. This indicates that caffeine is a biotransformation product of theophylline in premature neonates and that the metabolic pathway followed by theophylline in premature infants includes a methylation reaction producing caffeine, whereas in adults, the major metabolic pathway involves oxidative reactions (demethylation and oxidation). Some pharmacologic effects attributed to theophylline during chronic therapy for apnea may in part be due to caffeine. Routine monitoring during theophylline therapy in premature neonates with apnea should include plasma concentrations of both theophylline and caffeine in order to assess the total methylxanthine load.     

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     

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     

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.     

Theophylline absorption in young asthmatic children receiving sustained-release formulations

Theophylline absorption from sustained-release formulations intended for administration every 8 hours and every 12 hours was examined in children ages 2 to 6 years during multiple dosing intervals. By generally applied measurements, including mean serum theophylline concentration, bioavailability over a single daytime dosing interval, and percent change in serum theophylline concentration over a single dosing interval, the preparations did not differ. However, over multiple dosing intervals, the 8-hour preparation varied in rate and extent of absorption, with subsequent large variations in serum theophylline concentrations. The 12-hour preparation, on the other hand, was completely bioavailable during each dosing interval, although the rate of absorption did differ from day to night, and was associated with generally acceptable changes in serum concentrations. Thus, analysis of dose-to-dose absorption was required to reveal the differences between the two study preparations. This indicates that traditional analysis of a single daytime dosing interval may be inadequate in the evaluation of preparations of sustained-release theophylline.     

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.     

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.     

Rectal aminophylline in the management of apnoea of prematurity.

Rectal suppositories as an alternative to intravenous aminophylline in the management of recurrent apnoea were studied in 41 preterm infants of mean gestation 28.3 weeks and mean birthweight 1176 g. Therapeutic blood concentrations were obtained two hours after a rectal loading dose of 10 mg/kg, with steady concentrations and maximum reduction in apnoeic episodes (from a mean of 0.5 per hour to 0.09 per hour) within 24 hours on a maintenance dose of 10 mg/kg/day. There was good correlation between the rectal dose and the plasma theophylline concentration. Several infants showed a significant reduction in Pco2 when treated with aminophylline. Side effects were related to the plasma theophylline concentration and were not seen at concentrations less than 14 mg/l.     

Cardiac output changes secondary to theophylline therapy in preterm infants

The cardiovascular effects of theophylline were studied in 11 clinically stable preterm infants. Theophylline was given as aminophylline using a loading dose of 6.8 mg/kg and a maintenance dose of 2 mg/kg every 8 hours intravenously. Cardiac output, stroke volume, and heart rate were measured using a combination of pulsed Doppler ultrasound and M-mode echocardiography. Compared with day 0, an increase was found in both cardiac output (P less than 0.01) and stroke volume (P less than 0.02) on days 1, 2, and 3. By day 7, stroke volume was comparable to pretreatment values, whereas cardiac output was still increased. Heart rate was augmented significantly (P less than 0.01) throughout the treatment period. Mean arterial blood pressure did not change. All but one of the neonates had serum theophylline concentrations between 6 and 13 mg/L. We conclude that both inotropic and chronotropic effects are evident during the first days of theophylline therapy. The metabolic cost of the increased cardiac output in the preterm infant with theophylline therapy deserves further attention.     

Serum theophylline levels in asthmatic children after oral administration of two slow-release theophylline preparations.

Serum theophylline levels were measured throughout the day in 65 asthmatic children receiving one of two slow-release theophylline compounds. There was a wide interindividual variation in levels obtained with similar doses of pure theophylline, and also a wide intraindividaual variation in levels throughout the day, suggesting that the rates of release and/or absorption of theophylline from these compounds are not uniform. There were fewer side effects associated with taking these compounds than with choline theophyllinate.     

Acceptance of domiciliary theophylline monitoring using dried blood spots.

Filter paper cards incorporating dried blood spots for the measurement of theophylline concentrations were returned by 62 out of 100 asthmatic children sent kits with instructions for their collection. Analysis of the blood spots showed that 37 (61%) of the children who returned them had less than therapeutic blood theophylline concentrations, in 21 (34%) they were therapeutic, and in three (5%) they were potentially toxic. The results indicate that most asthmatic children would comply with requests for home monitoring of theophylline concentrations, and that only one third of children receiving theophylline achieved blood concentrations and that only one third of children receiving theophylline achieved blood concentrations within the therapeutic range.     

Plasma protein binding of theophylline during development in the rabbit.

The plasma protein binding profile of theophylline was investigated in the rabbit during the perinatal and developmental period. The roles of unbound plasma theophylline fraction (THu), albumin, nonesterified fatty acids (NEFA) and plasma bilirubin levels were analyzed. Plasma total protein and albumin levels doubled with age from the 1st day of life to maturity (from 3.1 to 5.3 and 1.6 to 3.7 g/l, respectively). THu, NEFA and bilirubin levels were inversely related to age, and decreased from 81 to 37%, 2,136 to 239 microEq/l and 2.4 to 0.20 mg/dl, respectively. A linear correlation was shown between THu and albumin, NEFA, and bilirubin plasma concentrations. Stepwise multiple linear regression analysis, including albumin, NEFA and bilirubin values as independent variables, identified NEFA as the variable explaining most of the variability in plasma protein binding of theophylline. Findings support the need for careful interpretation (with a view to therapeutic utilization) of estimates of plasma protein unbound fraction of a drug during development. This fact highlights the importance of considering not only protein but NEFA concentrations too.     

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.     

Oral theophylline dosage for the management of chronic asthma

Theophylline dosage requirements to maintain serum concentrations of 10 to 20 microgram/ml among asthmatic patients were examined in 156 children, ages 2 1/2 months to 16 years, and 33 otherwise health adults. Using 100% bioavailable preparations, low doses were used initially and increased, if tolerated, at three-day intervals. Final dosage was based on serum theophylline measurements which were subsequently repeated after six or more months of therapy. Dosage standardized by weight averaged 24.1 +/- 5.5 mg/kg/day (mean +/- SD) among the 77 children under age 9 years. Age-related variability of weight-adjusted doses were not observed for younger children, but average dose requirements decreased progressively beyound age 9 years to 13 mg/kg/day for patients beyoung 16 years of age. Although interpatient variability in dosage was confirmed at all ages, intrapatient variability in requirements over an average eight-month interval were small; dosage changes to maintain therapeutic serum concentration were primarily associated with growth. These data allow age-specific guidelines for dosage recommendations based on the likelihood of optimally effective and potentially toxic serum theophylline concentrations.     

Dose conversion from aminophylline to theophylline in preterm infants.

Twenty two preterm infants were prospectively evaluated to assess the need for dose adjustment when converting enteral and parenteral routes of methylxanthine administration. Serum theophylline concentrations remained unchanged in 18 infants after conversion from intravenous aminophylline to theophylline by mouth with dose reduction, as is currently recommended. Intravenous aminophylline and theophylline by mouth may therefore be prescribed at equivalent doses, with a possible reduction in drug errors, and improved stability of serum concentrations.     

A randomised, double blind, placebo controlled trial of the effect of theophylline in prevention of vasomotor nephropathy in very preterm neonates with respiratory distress syndrome

BACKGROUND: Vasomotor nephropathy is a common renal dysfunction in very preterm neonates. OBJECTIVE: To determine whether theophylline could prevent vasomotor nephropathy in very preterm infants with respiratory distress syndrome. METHODS: A randomised, double blind, placebo controlled trial of 50 preterm infants of gestational age < or = 32 weeks needing assisted ventilation. Infants received an intravenous dose of theophylline (1 mg/kg) or placebo for three days. The 24 hour urine volume was measured daily. On days 2, 5, and 11, blood samples and 12 hour urine collections were analysed for electrolytes, creatinine, and urea. RESULTS: On day 1, urine output was significantly higher in the theophylline (2.4 (0.9) ml/kg/h) than the placebo (1.6 (1.0) ml/kg/h; p = 0.023) group (values are mean (SD)). The incidence of oligoanuria was significantly lower in the theophylline treated (5%) than the placebo (33%) group. Twenty four hours after the first administration of theophylline/placebo, serum creatinine concentration was significantly lower in the theophylline (0.76 (0.23) mg/dl) than the placebo (1.0 (0.41) mg/dl; p = 0.025) group. On day 5 an increase in serum creatinine was observed in both groups. On day 11 a significant reduction in serum creatinine was observed, compared with day 5, with no difference between the two groups. CONCLUSION: The results suggest that, in very preterm infants with respiratory distress syndrome, early theophylline administration improves renal function during the first two days of life.     

Theophylline toxicity in children

Sixty-five cases of theophylline toxicity in children were reviewed. Vomiting, tachycardia, and central nervous system excitation were the most common manifestations. Seizure activity occurred in four acutely intoxicated children whose serum theophylline concentrations were less than 70 micrograms/ml. Two patients experienced visual hallucinations in association with high serum theophylline levels. Dosing errors accounted for the majority of cases. Most instances of toxicity could have been avoided by more careful consideration of the patient's medication history and more diligent monitoring of serum theophylline concentrations.     

Teratogenic Effect of Tedral (Theophylline, Ephedrine, and Phenobarbital) on Cardiac Development in Chick Embryos

Abstract We employed the chick embryo in a comparative study of the effect of Tedral and theophylline on anatomical development. Tedral, which contains theophylline in combination with ephedrine and phenobarbital in the relative dose ratio of theophylline 33: ephedrine 6: phenobarbital 2, or saline for control was dropped onto the surface of the chorioallantoic membrane of 2, 3, 4 and 5-day-old chick embryos. In groups A (theophylline 0.015 M, ephedrine 0.0027 M, phenobarbital 0.0009 M) and B (theophylline 0.011 M, ephedrine 0.0020 M, phenobarbital 0.0007 M), 100% of embryos treated on the 5th day of incubation developed aortic aneurysms with associated cardiovascular malformations. In group C (theophylline 0.005 M, ephedrine 0.0009 M, phenobarbital 0.0003 M), 36.8% of embryos treated on the 5th day of incubation developed aortic aneurysms, and 73.7% of embryos had cardiovascular malformations. These data were compared with those obtained by using theophylline, ephedrine or phenobarbital alone. The commonest cardiovascular anomalies induced by Tedral were double-outlet right ventricle with ventricular septal defect. Aneurysms were larger in size and cardiovascular malformations were more complex in embryos exposed to Tedral than in those treated with theophylline alone. Complex cardiac defects produced by Tedral included transposition of the great arteries, double-outlet right ventricle with double-inlet left ventricle, and truncus arteriosus communis. A slit-like small ventricular septal defect was found in 9.5% of the ephedrine-treated (0.51 mg) chick embryo group and 9.1% in the control embryos. These data show: (1) theophylline, a major component of Tedral, produces cardiovascular anomalies in embryonic chick hearts; (2) there is synergy of all three drugs in Tedral; (3) the specific type of conotruncal defect depends on the timing of administration, e.g., truncus arteriosus communis was produced on day 4 of Tedral administration in chick embryos.     

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.