Serum Theophylline Concentrations Research Articles

Theophylline poisoning. Pharmacological considerations and clinical management.

The recent marketing of slow release preparations of theophylline and new indications for the use of the drug have resulted in a marked increase in the sale of theophylline products. This phenomenon combined with the drug's highly variable pharmacokinetics has led to an increase in the number of theophylline intoxications. The morbidity and mortality rates associated with theophylline intoxication are significant. Therefore it is essential that clinicians are aware of the pathophysiology, clinical presentation and treatment of this poisoning. Theophylline intoxication mainly affects the gastrointestinal, cardiovascular and central nervous systems. Signs and symptoms range from mild gastrointestinal upset to serious central nervous system manifestations such as seizures, a symptom often associated with a bad prognosis. Theophylline serum concentrations are very useful for making decisions regarding treatment. However, their interpretation should take into account several factors such as the age of the patient and the type of intoxication (acute versus chronic). Prevention of gastrointestinal absorption should be the principal objective of treatment of an oral theophylline poisoning. The repetitive administration of activated charcoal not only prevents theophylline absorption but also increases its rate of Once absorbed, external methods such as haemodialysis and haemoperfusion can significantly accelerate the elimination of the drug from the body. Finally, the rapid suppression of seizures and cardiac arrhythmias are essential to prevent severe neurological sequelae and death. Since theophylline intoxication can be potentially life-threatening, its administration should be monitored with regular measurements of the serum theophylline concentration, especially in the very young and the very old.

Determination of the theophylline concentration in blood serum by the method of scanning UV spectrophotometry of thin-layer chromatograms

Determination of the theophylline concentration in blood serum by the method of scanning UV spectrophotometry of thin-layer chromatograms

The interaction between i.v. theophylline and chronic oral dosing with slow release nifedipine in volunteers.

Eight healthy volunteers received a 5 min i.v. infusion of lysine theophylline, equivalent to 197 mg anhydrous theophylline, both before (day 1) and during (day 5) steady state chronic oral dosing with slow release nifedipine 20 mg 12 hourly. A theophylline pharmacokinetic profile was performed on day 1 and day 5 and a nifedipine pharmacokinetic profile was performed on day 4 and day 5. The greatest difference in serum theophylline concentrations was seen at the first sampling time (5 min after completion of the infusion) with a mean concentration of 9.9 mg l-1 during nifedipine administration and 14.6 mg l-1 with theophylline alone. Thereafter, the difference fell to approximately 1 mg l-1 until 6 h when they became almost identical. Repeated measures analysis of variance using the theophylline serum concentrations at each of ten time points over 8 h as the repeated measures showed a small but significant effect of nifedipine (F(1,151) = 7.0, P less than 0.01) on serum theophylline concentrations. Mean volume of distribution (V) rose from 0.33 +/- 0.07 to 0.39 +/- 0.06 1 kg-1 corrected body weight (CBW) in the presence of nifedipine (t = 2.23, P = 0.052). Theophylline clearance, area under the curve to 8 h AUC (0-8), area under the curve to infinity AUC (0-infinity) and elimination half-life (t1/2) did not change appreciably. No statistically significant changes in nifedipine pharmacokinetics occurred in the presence of theophylline.

The absolute bioavailability of oral theophylline in patients with spinal cord injury.

The absolute bioavailability of oral theophylline in five tetraplegic, five paraplegic and three control (intact neuraxes) subjects was studied. All were healthy nonobese males between 20 and 60 years of age, with normal renal and hepatic function. More than 1 year had elapsed from the date of injury in all of the patients with spinal cord injury. None of the study subjects was taking medications known to interfere with theophylline metabolism or the analytic methodology. Each received theophylline in an equivalent amount orally, and by intravenous infusion on 2 occasions separated by not less than 2 weeks. The time course of serum theophylline concentration was followed for up to 24 hours and the area under each oral and intravenous curve extrapolated to infinity (AUC male infinity) was compared using a linear, least-squares, best-fit BASIC program (ESTRIP). A statistically significant difference between means and variances of the absolute bioavailability of oral theophylline, AUCoral male infinity/AUCIV male infinity, (AUCratio +/- SD) was demonstrated in the tetraplegic subjects who showed decreased bioavailability (AUCratio = 0.67 +/- 0.04, range 0.63-0.73) as compared to the paraplegic (AUCratio = 0.95 +/- 0.09, range 0.84-1.08) and control subjects (AUCratio = 0.90 +/- 0.12, range 0.78-1.02). A decrease in the bioavailability of oral theophylline in tetraplegic subjects has not previously been described and may be caused by impaired gastric emptying, which frequently characterizes high myelopathy. Diminished bioavailability could result in underestimation of loading and maintenance doses in tetraplegic humans.

血清中テオフィリン濃度測定のためのセラライザー法の評価

Seralyzer system applying apoenzyme reactivation immunoassay system for determination of serum theophylline concentration (SERALYZER method) was evaluated. The coefficients of variation of within-run and between-run precisions for 3 concentrations of theophylline in serum were less than 4%. The serum theophylline concentrations determined by SERALYZER method for 40 samples were compared with those determined by high-performance liquid chromatography (HPLC), substrate-labeled fluorescent immunoassay method-fluorostat (SLFIA method-A), SLFIA method-OPTIMATE (SLFIA method-B) and fluorescence polarization immunoassay method (FPIA method). There were good agreements between HPLC and SERALYZER method results, SLFIA method-A and SERALYZER method results, SLFIA method-B and SERALYZER method results, and FPIA method and SERALYZER method results, where all correlation coefficients were 0.996. The cross-reactivities of caffeine, 8-chlorotheophylline, 1, 3-dimethyluric acid, 1, 7-dimethylxanthine, 3-methylxanthine, theobromine, and 1, 3, 7-trimethyluric acid in SERALYZER method were found. However, these cross-reactivities are not serious problems in clinical condition. Therefore, the SERALYZER method may be useful for the drug-level monitoring of patients under theophylline therapy.

Circadian changes in the absorption and elimination of theophylline in patients with bronchial obstruction.

Circadian variation in the serum concentration of theophylline has been reported in most patients receiving slow release oral preparations. To examine further the mechanism and clinical relevance of this change, an investigation has been made into the diurnal fluctuation in elimination kinetics during i.v. administration of theophylline and its serum concentration profile on oral treatment with a slow release preparation, in 8 hospitalized patients receiving it for bronchial obstruction. After reaching steady-state on a constant intravenous infusion, the total body clearance of theophylline (CL) was determined every 4-6 h from the steady-state concentration and the infusion rate. No systematic trend indicative of circadian changes in elimination kinetics was observed. The intraindividual fluctuation in CL during the observation period was small (coefficient of variation 4-11%). In contrast, on oral dosing a smaller area under the serum concentration-time curve was found during the night time (22.00-06.00). The results show that the circadian variation described in serum theophylline concentrations is due to delayed absorption at night. The elimination kinetics of theophylline do not change.

Management of Pediatric Patients with Bronchiolitis in the Emergency Department

We evaluated the pattern and appropriateness of the use of drugs and laboratory data or procedures in 100 patients (average age: six months) with the diagnosis of bronchiolitis during 127 visits to the emergency department. Patients were selected randomly among those seen during 1983. All patients had usual signs and symptoms of bronchiolitis. Adrenergic drugs utilized were epinephrine 1:1000 during 30 visits, epinephrine suspension during 14 visits, metaproterenol during six visits and isoetharine during seven visits. Repeat doses of epinephrine were used in six cases. Therapeutic response to epinephrine was noted in 14 cases but not in nine cases. This information was not available in seven cases. Pulse rate and respiratory rate were measured in all cases. Chest x-rays were done in 46 percent, complete blood count in 19 percent and blood gases in 11 percent of the patients. Patients were sent home with instructions to take metaproterenol in 16 cases, theophylline in 19 cases, acetaminophen in 34 cases and cough preparations in 29 cases. Theophylline products were used in 19 cases. Theophylline dose ranged from 14–20 mg/kg/day except in two patients who received 24 and 40 mg/kg/day. Theophylline serum concentrations were determined in only two of 19 cases, and one value was unevaluable. Initial response to epinephrine was not documented in many cases who were sent home on continued therapy with metaproterenol or theophylline. Thirty-one cases returned for a follow-up visit to this hospital. These findings demonstrate that: (1) despite a lack of clear evidence of efficacy, a variety of pharmacologic agents were used; (2) serum concentration of theophylline were monitored infrequently; theophylline dose should be individualized based on its serum concentration to minimize potential toxicity; (3) laboratory data or procedures were utilized appropriately; and (4) most patients did not appear for a follow-up evaluation at this hospital for the assessment of drug efficacy, adverse effects and compliance.

外来ぜん息患者を対象としたＳｉｎｇｌｅ Ｐｏｉｎｔ採血によるテオフィリン投与設計の検討

It is desirable that theophylline dosage regimen is based on individual pharmacokinetic parameters for management of the outpatient with chronic asthma to avoid toxicity due to overdosage. This study was conducted to design theophylline dosage regimen by single serum sample monitoring.Four healthy volunteers were given choline theophylline 200 mg (theophylline 126.6mg) and serum theophylline concentration was measured 8 times (as specified) foi determining pharmacokinetic parameters. Average values of Ka (absorption rate constant), Vd (distribution volume), and Kel (excretion rate constant) were obtained to be 8.31/hr, 0.441 1/kg, and 0.081/hr, respectively. Individual theophylline dosage regimen was designed with these parameters. The predicted and measured concentrations of theophylline were compared with each other after multiple oral doses. The errors were within the range of -9.3 to + 12.1%. Asthmatic outpatient's Kel was calculated from single sample monitoring data and average values of Vd and Ka of healthy volunteers. Monitoring time was 4 hours after administration of choline theophylline to avoid the effect of Ka. A new dosage regimen was designed with these parameters for 14 asthmatic outpatients who had already taken theophylline. After changing dosage regimen the predicted concentrations were compared with the measured ones. The errors were within the range of -18.3 to + 18.5%, This method of theophylline dosage regimen by single serum sample monitoring is significantly useful in clinical practice to avoid the toxicity. It is applicable to design the dosage regimen of the drug with large values of Ka and Kel, and fixed value of Vd.

Accuracy of Bayesian Analysis in the Prediction of Serum Theophylline Concentrations

Accuracy of Bayesian Analysis in the Prediction of Serum Theophylline Concentrations

Atrial Arrhythmias Exacerbated by Theophylline: Response to Verapamil and Evidence for Triggered Activity in Man

A 75-year-old woman with acute respiratory failure due to pneumonia superimposed on bronchospastic chronic obstructive pulmonary disease and dilated cardiomyopathy developed multifocal and unifocal atrial tachycardia. Arrhythmia recurrence appeared to be dependent on reaching a critical but "nontoxic" serum theophylline concentration in the presence of high normal levels of digoxin. The arrhythmias responded to a decrease in serum theophylline concentration or to the administration of verapamil. The precipitation of the atrial arrhythmias by theophylline in the presence of digitalis, both of which may increase intracellular calcium and a dramatic response to verapamil, which inhibits calcium uptake and release, suggests that these arrhythmias may represent an example of "triggered activity" in man.

Computer prediction of serum theophylline concentrations in ambulatory patients.

This study assessed the ability of a computer program Simulated Kinetics (SIMKIN) to predict serum theophylline concentrations in ambulatory patients receiving oral theophylline. Data were collected by retrospective review of prospectively obtained data. A total of only 20 measured serum theophylline concentrations could be included in the study, although records of 195 patients were reviewed. An estimated patient compliance of 90-110% was required and was computed using prescription refill information. Predicted serum theophylline concentrations were generated for each patient by entering into the SIMKIN program the characteristics pertinent to theophylline disposition and the patient's theophylline dosing regimen. Actual and SIMKIN-predicted theophylline concentrations were compared by using simple linear regression and by constructing a 95% confidence interval around the mean prediction error and root mean squared error. The ability of SIMKIN to predict therapeutic category, i.e., subtherapeutic, therapeutic, or toxic, was assessed using Fisher's exact test. SIMKIN predictions of individual theophylline concentration were insufficiently accurate to replace confirmatory followup monitoring of actual levels. However, SIMKIN was able to predict the therapeutic category with 70% accuracy. We conclude that SIMKIN may be useful for categorizing a dose regimen of theophylline as therapeutic, but that it is of little use in predicting individual concentrations in outpatients when literature-averaged pharmacokinetic parameters are the sole criteria for prediction, and compliance cannot be accurately assessed.

Theophylline reduces the response to nasal challenge with antigen

A nasal challenge model of allergic rhinitis was used to determine if pretreatment with oral theophylline reduces histamine release in vivo. Ten subjects were entered into a double-blind, cross-over trial. The results showed that both the physiologic response (sneezing) (p = 0.02) and the amount of mediators (histamine, kinins, toluene sulfonyl arginine methyl ester esterase activity) (p <0.01 for all) released into nasal secretions were significantly reduced after one week of pretreatment with theophylline. At the time of challenge, the serum concentrations of theophylline were between 8 and 22 μg/ml. It is speculated that the ability of theophylline to block the clinical response to antigen challenge and to decrease the release of mast cell mediators contributes to its clinical efficacy in the treatment of asthma.

New method for bioavailability assessment of slow-release preparations of theophylline.

Variability in an individual's clearance of theophylline is an important consideration when estimating bioavailability. A method is described for compensating for this problem, using the serum concentration of theophylline and urinary excretion data on its major metabolites to make an estimation of the clearance after oral administration using the intravenous dose as reference. The method is particularly useful for assessing the bioavailability of slow-release theophylline preparations.

Comparison of morning and evening dosing with a 24-hour sustained-release theophylline, Uniphyl, for nocturnal asthma

Sixteen adults who had chronic asthma with nocturnal symptoms were selected to evaluate and compare the effectiveness of 7 A.M. versus 7 P.M. single daily dosing with the 24-hour sustained-release theophylline Uniphyl. The study was a randomized, double-blind, placebo-controlled trial in which the patients were given 800 mg of Uniphyl at either 7 A.M. or 7 P.M. for one week each. Serum theophylline levels showed significantly higher peak (18.1 ± 1.8 μg/ml versus 12.7 ± 1.2 μg/ml) and trough (12.4 ± 1.3 μg/ml versus 7.6 ± 1.0 μg/ml) concentrations during evening dosing. Furthermore, daily peak flow values were higher in the morning when Uniphyl was given at 7 P.M. Thus, nocturnal dosing with Uniphyl gives higher serum theophylline concentrations and, with this, better control of nocturnal asthma.

Comparison of intravenous and oral routes of theophylline loading in acute asthma

In a prospective, randomized clinical trial, 19 patients with an acute exacerbation of asthma were given a loading dose of aminophylline by the IV (n = 10) or oral route (n = 9) of administration following treatment with epinephrine. Plasma concentrations of theophylline were measured prior to giving the loading dose, and one, two, three, and 24 to 48 hours later. Therapeutic effectiveness was evaluated by analyzing spirometric measurements prior to giving the loading dose, and one, three, and 24 to 48 hours later. Side effects also were recorded. In the IV group, the mean peak plasma theophylline concentration was 15.1 micrograms/mL one hour after loading, and in the oral group the mean peak serum theophylline concentration was 14.2 micrograms/mL three hours after loading. There was no correlation between theophylline concentrations and normalized change in spirometric values. There was no significant difference in spirometric values between the IV and oral groups. Nausea was slightly more common in the IV group. We conclude that there is no therapeutic advantage to giving a loading dose of aminophylline by the IV route rather than orally in patients with mild-to-moderate exacerbation of asthma initially treated with epinephrine.

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.

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.

THEOPHYLLINE CONCENTRATION MEASUREMENTS IN SERUM OR SALIVA FOR THERAPY MONITORING IN BRONCHIAL ASTHMA

Theophylline concentrations in serum and in saliva obtained without and with stimulation (dil. citric acid) of 20 patients in the age range of 5-19 years on a long term theophylline therapy were simultaneously assessed within 6 hours after drug intake; at the same time several parameters of the lung function were taken. The theophylline concentration measurements were performed gaschromatographically. The saliva concentrations obtained without stimulation very strongly correlated with the serum concentrations (r=0,98; mean deviation from the regression line 0,70/ug/ml). The saliva concentrations obtained with stimulation revealed a significantly weaker correlation with the serum concentrations (r=0,82). A dependence of the concentrations from the salivation rate (m1/2 minutes) could be identified (r=0,66) in the saliva obtained with as well as in that obtained without stimulation; this dependence exists both intra- and interindividually. Reliability and evidence of the saliva concentrations obtained without stimulation can be further increased by measurement of the secreted saliva volume per period of time.

Evaluation of a mouse monoclonal antibody for the determination of serum theophylline by fluorescence polarization immunoassay.

Theophylline concentrations in spiked human serum and serum specimens obtained from patients with normal and impaired renal function were measured by fluorescence polarization immunoassay (FPIA) using a mouse monoclonal antitheophylline antibody. The interday coefficients of variation of the assay after 14 days were 4.2, 3.3, and 2.4% at serum theophylline concentrations in pooled human serum of 7.1, 12.2 and 26.9 mg/L. Theophylline concentrations determined by FPIA and high performance liquid chromatography (HPLC) were used to generate the following linear regression equations relating the corresponding theophylline concentrations measured by each method in serum specimens from 50 patients with normal renal function (FPIA = 1.00 HPLC + 1.01, r = 0.98) and 50 patients with end-stage renal disease (FPIA = 1.04 HPLC + 0.08, r = 0.99). In contrast to previous studies performed with a polyclonal antitheophylline antibody, the precision, accuracy, and specificity of the FPIA were adequate for analysis of theophylline in serum specimens obtained from patients with end-stage renal disease.

Theophylline concentrations in serum, plasma, and whole blood compared.

Journal Article Theophylline concentrations in serum, plasma, and whole blood compared. Get access L A Ferron, L A Ferron Search for other works by this author on: Oxford Academic Google Scholar J P Weber, J P Weber Search for other works by this author on: Oxford Academic Google Scholar J Hébert, J Hébert Search for other works by this author on: Oxford Academic Google Scholar P M Bédard P M Bédard Search for other works by this author on: Oxford Academic Google Scholar Clinical Chemistry, Volume 31, Issue 8, 1 August 1985, Pages 1415–1416, https://doi.org/10.1093/clinchem/31.8.1415 Published: 01 August 1985