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.     

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.     

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.     

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.     

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.     

Gastrin Secretion in Infancy and Childhood|Part 2: Gastrin Secretion in Gastrointestinal Diseases

Serum gastrin levels were measured radioimmunologically in 123 patients with various gastrointestinal diseases to study the pathophysiological role in the diseases.

• 1) In winter diarrhea, mean fasting gastrin level tended to be slightly higher in the severer patients but the difference from the control level were not statistically significant. After test meal, however, mean serum gastrin level increased rapidly and reached a peak by after 10 minutes followed by levelling off for 20 minutes. This result may suggest that a feedback mechanism between the secretion of gastrin and secretin is disturbed in the disease.
• 2) In bacillary dysentery, mean fasting serum gastrin levels in the acute stage did not differ from that of controls.
• 3) Mean fasting serum gastrin levels in neonatal hepatitis and chronic hepatitis of school children were significantly lower but the level in congenital biliary atresia was not different as compared to those of age-matched controls. Further investigation of gastrin metabolism in liver may be needed.
• 4) In duodenal ulcer, mean fasting serum gastrin level was not different statistically from the control value but mean gastrin response to feeding was significantly greater and longer than that of controls. This abnormality of gastrin release in children with duodenal ulcer may have a significant role in the pathogenesis of the disease.
• 5) In superior mesenteric artery syndrome, mean fasting gastrin level was significantly lower than that of controls and mean serum gastrin responses to test meal both in sitting and prone positions were significantly lower than those of controls. No statistical difference was found when the response were compared between in a sitting and prone positions. The hypogastrinemic response to meal in patients with this order was probably considered to be due to impaired function of G-cells which was caused by dilatation of the stomach and/or duodenum resulting in the mucosal damage.
• 6) The increment of gastrin secretion following glucocorticoid administration was found in children with anaphylactoid purpura and the effect was confirmed in rats. This results suggest that the so-called steroid ulcer may partly be caused by steroid induced gastrin hypersecretion.

     

Prophylactic theophylline infusion for prevention of apnea of prematurity.

To assess if there was any advantage in the prophylactic use of theophylline to prevent apnea in preterms, we treated 56 preterms (Group A) < 34 weeks gestation with theophylline infusion and compared these with 25 age and weight matched preterms (Group B) who received no therapy. Aminophylline (25 mg/ml) was infused from admission in all neonates (group A) at rates ranging 0.2 to 0.38 mg/kg/h and blood levels estimated on an Abbots TDX analyser by Fluorescence Polarization Immunoassay, after 5 days infusion. All neonates (Groups A + B) were monitored on a Corometric 505 neonatal monitor. In Group A, 1/48 developed primary apnea while in Group B, 4-21 had primary apnea (p < 0.05). Serum theophylline ranged from 2.3 to 39.5 micrograms/ml with a mean of 12.7 micrograms/ml. The mean serum level of theophylline in 4 cases who exhibited clinical evidences of toxicity was 30.1 micrograms/ml. A statistically significant difference (p < 0.05) was noted in birth weight and serum level inspite of similar infusion rates of theophylline. A linear correlation r = 0.65 was noted between serum level and infusion rate. Multivariate regression analysis, between birth weight and gestational age to serum level, showed a linear correlationship only between birth weight and serum level (r = 0.45).     

Studies on Phagocytic Activity of Polymorphonuclear Leukocyte in Childhood Part 1. Phagocytic activity of PMNs in malnourished rabbits

To clarify the causes of reduced resistance to infection in children with malnutrition, the author carried out an experimental study. The phagocytic activity of PMNs, cyclic nucleotides in PMNs and plasma, total protein, IgG, total lipid, triglyceride, NEFA, and iron in sera were measured in starved rabbits and the following results were obtained:

• 1) After 4 weeks of starvation, the phagocytic activity of PMNs began to decrease and reached a minimum in the 5th week of starvation. Activity returned to normal with improving nutritional states.
• 2) The cyclic nucleotide levels in PMNs and serum abruptly increased in the 4th week of starvation and rapidly returned to normal with sufficient foot intake. The level of CAMP in PMNs and in serum was statistically inversely correlated with the phagocytic activity of PMNs during the experiment.
• 3) The levels of triglyceride and NEFA in serum were reduced in malnutrition. A positive correlation between the phagocytic activity of PMNs and serum triglyceride levels in serum was found.
• 4) A positive correlation between phagocytic activity of PMNs and IgG levels in serum was also observed.
• 5) The levels of total protein, iron, and total lipids in serum showed no change in malnutrition, so consequently no significant relationship between these levels and the phagocytic activity of PMNs was observed.
• 6) The serum of rabbits with malnutrition did not inhibit the phagocytic activity of control rabbits.

In brief, the present experiment revealed that reduction of the phagocytic activity of PMNs in starvation may be principally due to an increase in intracellular cAMP. (Acta Paediatr Jpn 23(2): 143–151 1981)     

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.     

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.     

The indication and effectiveness of low‐dose erythromycin therapy in pediatric patients with bronchial asthma*

Korematsu S, Yamamoto K, Nagakura T, Miyahara H, Okazaki N, Akiyoshi K, Maeda T, Suenobu S‐i, Izumi T. The indication and effectiveness of low‐dose erythromycin therapy in pediatric patients with bronchial asthma.
Pediatr Allergy Immunol 2010: 21: 489–492.
© 2010 John Wiley & Sons A/S To elucidate the mechanisms of intractable pediatric bronchial asthma and the indication of low‐dose erythromycin (EM) therapy, the serum chemokine levels of and the angiogenic factor were evaluated in 55 pediatric patients with bronchial asthma; 7.4 ± 3.5 yr old, who had been treated with inhaled steroid, leukotriene receptor antagonist, theophylline and others for more than a year. Both the levels of interleukin (IL) 8 (p = 0.036) and vascular endothelial growth factor (VEGF) (p = 0.005) were higher in patients with severe type than those of patients with the milder type, while other chemokine levels such as serum eotaxin and MCP1 did not show the correlation with the severity of bronchial asthma. Induction of therapy with low‐dose EM induced improvement of the clinical symptoms in patients with severe type and decrease of their serum chemokine levels: IL8; from 736 ± 88 to 75 ± 85 pg/ml (p < 0.0005), and VEGF; from 352.0 ± 160.5 to 132.2 ± 59.9 pg/ml (p = 0.021) within the next 6 months. Moreover, low‐dose EM resulted in a decreased daily peak‐trough fluctuation rate of the serum theophylline concentration; (C_max ? C_min)/C_min, from 1.3 ± 0.5 to 0.5 ± 0.3, which led to the maintenance of effective serum levels. These results indicated that IL8 and VEGF affect the severity of standard therapies resistance intractable bronchial asthma. Through the suppression of these chemokines and maintenance of effective theophylline levels, low‐dose EM therapy improves the symptoms of bronchial asthma.     

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 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     

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.     

Veränderungen der Serumphospholipide bei Hepatitis infectiosa im Kindesalter

The serum phospholipids (separation by thin layer chromatography) were studied in 22 children with infectious hepatitis; a characteristic change was observed during the acute stage:

1. The level of total serum phospholipids was significantly increased to an average of 167.8 μg/ml (SD±22.3 μg/ml) compared to a control group of 20 healthy children who had a mean concentration of 69.4 μg/ml (SD±10.5 μg/ml; P<0.001). Like the other parameters described here the values for total phospholipids returned to normal levels within 20 days from the beginning of treatment (68.7 μg/ml; SD±14.1 μg/ml).
2. The most obvious change among the phospholipid fractions was a significant rise in lecithine. In acute hepatitis serum the lecithine fraction amounted to a mean value of 126.3 μg/ml (SD±20.0 μg/ml) i.e. 73% of the total phospholipids.
3. The absolute values for sphingomyeline and lysolecthine were higher than normal; however, the relative values for these two fractions were shown to be lower than normal.
4. Therefore it seems to be serum lecithine which is responsible for the behaviour of the total phospholipids. In contrast to other investigators we found in our patients that the smallest deviations from normal values were observed in cephaline and lysolecithine. Although lysolecithine is considered a sensitive indicator for disturbances of the liver parenchyma it seemed to be affected to a lesser degree by hepatitis than the lecithine fraction.
5. In agreement with other biochemical and clinical findings the abnormalities in the ratio of the various phospholipids could no longer be demonstrated when serum samples were examined after 20 days of treatment.
6. To a large extent the changes in serum phospholipids seem to be the result of a defective membrane function in the liver cell during acute hepatitis. Thus an increased release of lecithine and other phospholipids into the extracellular space may occur. Since obstructive jaundice is usually accompained by high serum concentrations of lecithine and free cholesterol the possibility exists that a transitory bile retention plays a certain part in acute hepatitis.

     

Effect of Single Dose Intravenous Animophylline in Asthma

Fifty-five children with acute asthma were studied to evaluate the relationship between pulmonary function (improvement in forced expiratory volume in one second, FEVj, and maximum flow at 50% vital capacity, V₅₀) and serum theophylline concentration after intravenous aminophylline. Serum theophylline concentrations and pulmonary function were measured before and after aminophylline therapy. In our study, there was significant improvement in pulmonary function in patients whose baseline serum theophylline concentration was under 5 ng per ml, when their post-infusion levels reached 10 to 15 μg per ml. Significant improvement in pulmonary function was noted in subjects whose baseline FEV₁ was under 50% of the predicted value when their post-infusion serum theophylline levels rose to 10 to 15 μg per ml.     

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.     

Prevention of apnea and bradycardia in low-birthweight infants.

The efficacy of theophylline in preventing severe apnea was evaluated in 17 low-birthweight infants (mean weight, 1,400 gm). Apnea was detected and accurately quantified by 13-hour pneumogram recordings and correlated with serum theophylline levels. Nursing observations coupled with on-line alarm systems detected only 39% of severe apneic episodes as compared to the pneumogram recording technique. Theophylline in six hourly oral doses(1.5 to 4.0 mg/kg) yielded two-hour serum concentrations of 6.6 to 11.0 mug/ml which completely controlled apneic spells exceeding 20 seconds in duration and markedly reduced 10- 19-second apneic episodes and any resultant bradycardia. At these serum levels, toxicity was not observed. Therapy with theophylline should be instituted at a dose of 2 to 3 mg/kg every six hours and the optimum therapeutic dose should be individualized as determined by objective quantitation of apnea and serum theophylline concentration.     

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.     

Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial

OBJECTIVE: To study whether prophylactic theophylline can reduce the incidence and/or severity of renal failure in term infants with perinatal asphyxia. STUDY DESIGN: Term neonates with severe perinatal asphyxia were randomized to receive a single dose of either theophylline (study group, n = 40) or placebo (control group, n = 30) during the first hour of life. Daily weight, output/input ratio, 24-hour fluid intake, and urine volumes were recorded during the first 5 days of life. Those infants with asphyxial renal failure were followed up for 1 year. RESULTS: The incidence of severe renal dysfunction was increased in the control group. Creatinine clearance was higher and excretion of beta 2 microglobulin (beta2M) was lower in the theophylline group. Conversely, the glomerular filtration rate was lower in the control group. In infants with renal failure, serum creatinine and creatinine clearance returned to normal in the neonatal period, and the increased beta2M excretion normalized by age 6 weeks. CONCLUSIONS: A single dose of theophylline within the first hour of birth in term neonates with perinatal asphyxia results in a significant decrease in serum creatinine level and urinary excretion of beta2M, along with an increase in creatinine clearance.