Monitoring theophylline therapy using citric acid-stimulated saliva in infants and children with asthma

Saliva stimulation is required for measurement of drugs in saliva. Chewing on a piece of paraffin, which is the method usually used for saliva stimulation, requires cooperation of the patient and, thus, is inapplicable in infants and young children. To assess the value of determining theophylline concentrations from noninvasively obtained saliva in this age group, we studied the theophylline plasma to saliva concentration ratio in citric acid-stimulated saliva. Theophylline concentration was measured in 137 simultaneously obtained paired specimens of plasma and saliva from 68 patients 2 1/2 months to 14 years of age treated with theophylline for asthma (dosage 20.8 +/- 5.2 mg/kg/d, mean +/- SD). Saliva secretion was stimulated by placing citric acid crystals on the tongue. A strong and highly significant correlation was observed between both determinations (r = .96; P less than .01). The plasma to saliva ratio was 1.78 +/- 0.22 (mean +/- SD), with theophylline concentrations between 3.1 and 32.1 micrograms/mL of plasma. The ratio of estimated to actual plasma theophylline concentrations was 1.02 +/- 0.12 (mean +/- SD). Interindividual coefficient of variation of plasma to saliva theophylline concentrations ratios was 12.4%; mean intraindividual coefficient of variation was 5.3%. The use of citric acid for saliva stimulation is easily applicable to infants and young children. Compared with blood drawing, stimulation of saliva secretion by citric acid is painless and noninvasive, is more readily accepted to patients, is at least as clinically relevant for theophylline determination, and allows frequent measurements of drug levels for individualization of the dosage with samples taken at home.(ABSTRACT TRUNCATED AT 250 WORDS)     

Re-evaluation of saliva for monitoring theophylline concentrations.

Variability of the mixed saliva/plasma theophylline relation was examined in seven children aged 2 to 13 years. Good correlation between plasma and saliva concentrations was found, but on the three occasions there was considerable inter- and intrapatient variability. There was no significant or consistent relation between unstimulated and stimulated saliva concentrations or between saliva concentrations and sample volumes. Plasma theophylline concentrations cannot be predicted accurately from saliva values.     

Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels.

A group of ambulatory asthmatic children was studied with serum and salivary theophylline levels following a prescribed dose of a hydroalcoholic solution of theophylline to determine compliance. The gas chromatographic procedure used was both selective and sensitive for theophylline without the necessity of withholding coffee, tea, chocolate, or cocoa. In the first group of patients, only 11% achieved therapeutic levels, 65% had less than therapeutic levels, and 23% had no measurable drug in saliva. With more directive and supervised drug administration in a second group of patients, 42% achieved therapeutic levels, 51% were below therapeutic levels, and only 6% had no measurable drug. Monitoring patients with salivary theophylline levels proved an effective way of improving compliance and also alerted physicians to noncompliance as a possible explanation of "treatment failure". Salivary specimens are readily obtained and noninvasive so that the technique is readily adaptable for use in the office of clinic setting.     

Lack of effect of respiratory syncytial virus infection on theophylline disposition in children.

Conflicting reports raise a question about decreased plasma clearance (Clp) of theophylline in man during viral infections. Thus a dilemma exists concerning requisite dose adjustments. We examined this issue by retrospectively evaluating theophylline Clp in children infected with respiratory syncytial virus (RSV). Two pharmacokinetic approaches were applied to a one-compartment open model to fit theophylline concentrations during 83 hospitalizations of 76 children, 6 to 48 months of age, who received intravenous theophylline therapy and were tested for RSV infection. Iterative linear regression analyses of all theophylline data were used to estimate apparent volume of distribution, elimination rate constant, plasma half-life, and Clp in 39 of the hospitalizations. When insufficient data were available to distinguish apparent volume of distribution and elimination rate constant (n = 44), steady-state estimates of Clp were calculated. An age-matched and percentile body weight-matched cohort design presented RSV as the primary covariate. Theophylline Clp was similar in 29 matched RSV-infected and -uninfected pairs (1.32 +/- 0.14 and 1.25 +/- 0.05 ml/kg per minute, respectively), as were other pharmacokinetic values. Unexpectedly, a significant, inverse linear relationship was found for Clp and percentile body weight. Additionally, children born prematurely and hospitalized in the neonatal intensive care unit had significantly higher theophylline Clp; this did not affect findings regarding RSV infection. Theophylline Clp was not decreased in RSV-infected children. Current theophylline dosing recommendations for young children infected with RSV should not be altered, but careful monitoring of plasma theophylline levels should be continued.     

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.     

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     

Use of saliva in monitoring carbamazepine medication in epileptic children

In 17 children on carbamazepine medication alone and 15 children on combined drug regimens, carbamazepine levels were determined in paired samples of serum and mixed saliva by enzyme immunoassay. Carbamazepine levels in serum and saliva were highly correlated in within-patient and between-patient series (r=0.87–0.94). Salivary levels were altered to a minor and clinically insignificant degree by stimulation of saliva flow. Mean saliva/serum ratios, calculated from drug concentrations in saliva specimens collected without and with stimulation were 0.44–0.45 and 0.41–0.43, respectively. The saliva/serum ratio was independent of the serum carbamazepine level and was not affected by concomitant drug medication. The data indicate that measuring salivary levels by enzyme immunoassay is suitable for predicting serum carbamazepine levels. Thus, measurement of carbamazepine levels in mixed saliva samples obtained by a noninvasive technique is recommended for routine monitoring of carbamazepine medication in epileptic children.Supported by Deutsche Forschungsgemeinschaft (Ba 246/11)The data comprise part of the doctoral thesis of Elke Günther, University of Kiel     

Effect of inhaled beclomethasone dipropionate on saliva cortisol concentrations.

Serial saliva cortisol measurements were used to assess pituitary-adrenal function in a group of asthmatic children treated with beclomethasone dipropionate (400 micrograms daily). Asthmatic children who were not being treated with steroids and normal children were also studied for comparison. A diurnal cortisol rhythm was observed in all three groups. Early morning cortisol concentrations were significantly higher in the group treated with beclomethasone dipropionate than in the normal children; this may indicate a stress induced response to decreased morning peak expiratory flow. In both groups, plasma and salivary cortisol responses after adrenocorticotrophic hormone stimulation test were normal but peak cortisol concentrations showed a 7 fold increase over basal values in saliva compared with a three fold increase in plasma. Beclomethasone dipropionate does not suppress pituitary-adrenal function in children when used in recommended doses. Serial measurement of the salivary cortisol concentration is a simple, safe, and sensitive method for the routine monitoring of adrenal function in children treated with this steroid. Monitoring may be supplemented with an assessment of the adrenal response to adrenocorticotrophic hormone stimulation, if necessary.     

Plasma xanthine levels in low birthweight infants treated or not treated with theophylline.

The use of theophylline in the management of apnoea in the newborn was studied in 33 preterm infants. Infants received a dose of 3 mg/kg, 13 of them every six hours, the remaining 20 every eight hours. All the infants had significantly fewer apnoeic episodes. In a pharmacokinetic study, the half life of theophylline was 30.3 +/- 7.2 hours and the clearance rate was 23.9 +/- 5.06 ml/kg per hour (means and SD). The plasma theophylline level remained constant at between 13 and 15 mg/l from the 5th day of treatment but, at the same time, the plasma levels of caffeine rose to a mean level of 4.4 mg/l. Caffeine was detectable in plasma at birth, and in preterm infants not receiving theophylline; plasma levels of caffeine tended to be similar to the levels in their mothers' milk. These observations have led to clear conclusions on the optimum timing and dosage of theophylline, and on the need to monitor plasma levels of both theophylline and caffeine in newborn infants treated with theophylline.     

Theophylline metabolism in acute asthma with MxA-indicated viral infection

BACKGROUND: Although viral infection might alter theophylline metabolism in acute asthma, there are some difficulties in detecting infection due to various kinds of viruses in a clinical setting. METHODS: To evaluate the usefulness of assessment of MxA protein in acute asthma exacerbated by viral infection, MxA protein expression in lymphocytes was assayed by flow cytometric analysis in whole peripheral blood in 21 children (aged 0-6 years) receiving continuous theophylline infusion for management of asthma attack. Serum theophylline levels were measured at 24 and 72 h after initiating theophylline infusion. RESULTS: At the beginning of theophylline infusion, 11 children had increased expression of MxA protein, indicating viral infected states. After 24 h continuous infusion, there were no differences in theophylline levels between MxA-negative and MxA-positive groups. After 72 h infusion, the mean theophylline level of MxA-positive children was significantly higher than that of MxA-negative children (9.7 +/- 2.2 microg/mL vs 7.3 +/- 1.6 microg/mL). The ratio of theophylline clearance at 72 h to that at 24 h in the MxA-positive group was significantly lower than that of the MxA-negative group (1.1 +/- 0.2 vs 1.4 +/- 0.1). CONCLUSIONS: Viral infection appeared to affect theophylline metabolism. Flow cytometric assay of lymphoid MxA protein expression in whole blood is an easy and useful method of evaluating viral infection in acute asthma exacerbation.     

Effect of therapeutic plasma concentrations of theophylline on behavior, cognitive processing, and affect in children with asthma

A double-blind, randomized, crossover study assessed the effects of theophylline on behavior, mood, and efficiency of cognitive processing. Thirty-one children aged 8 to 12 years with moderate asthma were randomly assigned to 10-day theophylline followed by placebo or to placebo followed by theophylline experimental conditions separated by 2-day washout periods. Theophylline plasma concentrations and pulmonary function tests were performed throughout the study. Cognitive functioning tests and self-report measures were administered at baseline and after each medication phase. Behavior ratings were obtained from parents and teachers. Parents' and teachers' ratings did not reflect a theophylline effect on attention or activity level; children's self-reports showed no changes in mood, and no statistically significant differences were found on measures of cognitive processing. Large individual differences in sensitivity to theophylline effects were present. Although most of the children tolerated theophylline well, those already having attentional or achievement problems appeared vulnerable to adverse effects. Individual response differences should be a focus of future studies.     

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.     

小剂量茶碱配合吸入皮质激素治疗小儿哮喘的疗效评价

目的研究小剂量茶碱与皮质激素治疗小儿哮喘的协同抗炎作用。方法选择80例中度小儿哮喘,随机分为治疗组、对照组(各40例),治疗组口服小剂量茶碱控释片(或胶囊)配合吸入必酮碟,对照组只吸入必酮碟。结果治疗组在皮质激素较快减量过程中的峰值流速(PEFR)始终在预计值的80％以上,皮质激素的维持量明显较对照组小。结论小剂量茶碱配合吸入皮质激素,可使皮质激素减量过程快,维持剂量小,茶碱的不良反应少,不必强调血药浓度的监测。     

The biologic significance of the aldosterone concentration in saliva.

Salivary aldosterone measurements can be used to study aldosterone secretion and metabolism noninvasively. Salvia and plasma aldosterone concentration were highly correlated during all periods of study; during adrenocorticotrophic hormone (ACTH) administration, a relatively greater amount of aldosterone appeared in saliva; during dexamethasone administration, a relatively smaller amount of aldosterone appeared in saliva. As plasma cortisol increased with ACTH administration there was an increased relative amount of aldosterone in saliva. DOC (11-deoxycorticosterone) was found in saliva only during ACTH administration. Corticosterone was identified during baseline periods. Salivary aldosterone concentrations were independent of flow. The data indicate that saliva is an accessible bodily fluid which may be used to monitor the changes in nonprotein bound plasma steroid hormone concentration in children.     

Titres of specific antibodies to poliovirus type 3 and tetanus toxoid in saliva and serum of children with recurrent upper respiratory tract infections

A study of antibody levels (in saliva and blood) against common vaccine antigens was performed in a population of 32 children suffering from recurrent upper respiratory tract infections (URTI). None of the patients had primary or secondary immunodeficiency syndromes or other known predisposing factors for respiratory diseases. Titres of the isotype-specific antibodies immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) against two vaccine antigens – poliovirus type 3 (P3) and tetanus toxoid (TT), a viral antigen and a bacterial antigen, respectively – were measured in unstimulated saliva and serum, both in patients and in 24 healthy children (controls), by using a standard enzyme-linked immunosorbent assay (ELISA). In addition, levels of total IgA and avidity of IgA antibodies to both P3 and TT in saliva were evaluated. No difference was found between patients and controls as to levels of total IgA, or specific IgA and IgM antibodies against both P3 and TT in saliva. Furthermore, the avidity of salivary IgA antibodies against the two antigens did not differ between the two populations. However, the average concentrations of saliva-specific IgG antibodies to both the viral and the bacterial antigen were significantly lower (p < 0.01 for P3 and p < 0.05 for TT, respectively) in saliva of children with recurrent URTI, whereas no difference was found in serum for any immunoglobulin isotype determined compared with healthy individuals. The results of the present study provide suggestive evidence for the existence of subtle IgG-restricted defects in antibody responses at the mucosal level, but not at the serum level, in some children with undue susceptibility to URTI.     

Behavior abnormalities and poor school performance due to oral theophylline use

Studies evaluating adverse effects of oral theophylline on learning and behavior have been performed on children with asthma receiving long-term theophylline therapy. To further differentiate the effects of asthma itself from the drugs used, we evaluated 20 asthmatic children (6 to 12 years of age) who had not received oral bronchodilators for at least 6 months. A double blind, placebo-controlled, parallel format was used with a 4-week theophylline or placebo period preceded by a 2-week baseline. Theophylline serum levels were maintained between 10 to 20 micrograms/mL. During baseline and treatment periods, the child's home and school behavior/performance were monitored independently by their parents and teachers using standardized report forms. A battery of psychologic tests was administered at the end of baseline and treatment periods. Seven children receiving theophylline were noted to have a change in school behavior and/or performance during their 4 weeks on drug compared to baseline, whereas none of the children receiving placebo were noted to be different (P = .004). Thus, the short-term administration of theophylline to asymptomatic asthmatic children not receiving oral bronchodilators can adversely affect school performance and behavior. Because this population represents the majority of asthmatic children, one needs to use theophylline cautiously in this age group, monitor school performance closely, or seek other treatment modalities.     

Psychosocial aspects of compliance in children and adolescents with asthma

Thirty-eight children and adolescents (ages 7-17 years) with chronic asthma were evaluated on three measures of psychosocial and family adjustment. The children's average theophylline level and percentage of noncompliant theophylline levels (theophylline level less than 5 mg/dl) were correlated with behavior problems, perceived self-competence in controlling their conduct, general feelings of self-worth, and family climate (cohesiveness vs. conflict; level of family organization and control). Regression analyses indicated that a combination of psychological adjustment, degree of family conflict versus cohesiveness, and the interaction of these two variables were predictive of compliance as measured by mean theophylline levels. Only psychological adjustment was associated with percent of noncompliant theophylline levels. Measures of self-worth, self-competence in controlling conduct, and family organization were not related to medication compliance measures.     

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.     

Percutaneous administration of theophylline in the preterm infant

The preterm infant's skin is a poor barrier to the absorption of chemical agents. The possibility of turning this to the infant's advantage was explored by using the percutaneous route to administer theophylline. A standard dose of theophylline gel, equivalent to 17 mg anhydrous theophylline, was applied to an area of skin 2 cm in diameter over the upper abdomen under an occlusive dressing, and serial theophylline levels were measured; 25 studies were performed in 20 infants of less than or equal to 30 weeks gestation. Therapeutic theophylline levels (greater than 4 mg/L) were achieved in 11 of 13 infants who had not previously received the drug, and were maintained for up to 72 hours. In 12 studies in infants who were previously receiving aminophylline intravenously, theophylline levels were maintained for up to 70 hours. There was a significant decline in the amount of theophylline absorbed in the first 24 hours after application as the infant's postnatal age increased, but satisfactory blood levels were achieved in infants up to 20 days of age. The percutaneous route is a feasible method of administering theophylline in preterm infants.