Theophylline Levels Research Articles

Correlations between theophylline concentrations in plasma, erythrocytes and cantharides-induced blister fluid and peak expiratory flow in asthma patients

Theophylline levels in plasma, erythrocytes and cantharides-induced blister fluid (BF) have been correlated with peak expiratory flow (PEF) in asthmatic patients. Nine asthmatic men received an IV infusion of 240 mg theophylline at a constant rate for 30 min. The theophylline concentrations in erythrocytes and blister fluid were 37% and 78% of those in plasma. There was not a strong correlation between erythrocyte or blister fluid penetration and the clinical effect of theophylline.

Failure of gastric emptying and charcoal administration in fatal sustained-release theophylline overdose: Pharmacobezoar formation

We report the case of a fatal theophylline overdose from a sustained-release preparation in a 54-year-old woman. Initial serum theophylline concentration was 31.3 mg/L. Manifestations of mild toxicity cleared in the emergency department after treatment with gastric lavage, charcoal, and a cathartic. A life-threatening overdose was not suspected, and the patient arrested eight hours after discharge from the ED. At autopsy, her serum theophylline concentration was 190.1 mg/L. A white, waxy mass weighing 318.8 g and containing 29 g theophylline, representing the residue of many sustained-release tablets, was found in her stomach. This case reinforces the importance of obtaining repeat serum theophylline levels in patients with sustained-release theophylline overdose. Gastric pharmacobezoar formation should be considered in cases of sustained-release theophylline overdose with rising theophylline levels and patient deterioration, despite adequate gut decontamination.

Clearance of Theophylline by Hemodialysis in One Patient with Chronic Renal Failure

The clearance of theophylline by hemodialysis was determined in one patient who had polycystic kidney with chronic renal failure and bronchial asthma. The serum levels of theophylline were determined by enzymatic immunoassay on two consecutive days, once on a dialysis day and again on a nondialysis day. Clearance of theophylline by hemodialysis was 119 ml/min, and the extraction efficiency was 0.56. The elimination half-life of theophylline shortened from 5.7 h to 1.6 h during hemodialysis. The dialysis rate constant (Kd) was 0.32/h, and 79 percent of the total body store of the drug was removed during a 4-h dialysis. Patients receiving theophylline who are maintained on hemodialysis should be closely monitored for bronchospasm during and after the hemodialysis procedure. Measurement of serum concentrations of theophylline should be employed to facilitate increases in dosage during hemodialysis.

Whole-bowel irrigation as adjunctive treatment for sustained-release theophylline overdose

To determine a therapeutic benefit for whole-bowel irrigation (with polyethylene glycol-electrolyte lavage solution) as adjunctive treatment to multiple doses of activated charcoal following an overdose of sustained-release theophylline. Randomized crossover study. Three treatment arms were separated by one-week intervals. Animal care facility housing. Eight female mongrel dogs. Unanesthetized dogs were given approximately 75 mg/kg of sustained-release theophylline. In treatment arm 1, 1 g/kg activated charcoal was administered by nasogastric tube at two hours after ingestion followed by 0.5-g/kg doses at five and eight hours. During treatment arm 2, beginning two hours after theophylline ingestion, 25 mL/kg whole-bowel irrigation solution was administered every 45 minutes for four doses followed by activated charcoal. In treatment arm 3, the first dose of activated charcoal was given ten minutes before beginning the whole-bowel irrigation protocol. Serum theophylline levels were measured at zero, two, four, five, eight, 12, 16, and 24 hours after ingestion. Mean serum theophylline levels, area under the curve (P = .13), and terminal half-lives (P = .69) for each treatment group were not statistically different. This negative study had an 81% power to detect a 50% reduction in the area under the curve by whole-bowel irrigation treatment. In this model, whole-bowel irrigation did not add to the therapeutic benefits of activated charcoal.

Effect of methylxanthines on diaphragmatic fatigue in the piglet.

Studies in adult animal and human subjects have suggested that the methylxanthine drugs can delay the onset or attenuate the severity of diaphragmatic fatigue. We have investigated the effect of aminophylline and caffeine on the pressure-generating capacity of the fatigued diaphragm in 1-mo-old piglets. Measurements of ventilation, transdiaphragmatic pressure, blood gases and pH, diaphragmatic electromyogram, diaphragmatic pressure-frequency curve (PdiFC), diaphragmatic blood flow, and end-expiratory lung volume were obtained at baseline, after 90 min of inspiratory resistive loaded breathing (IRL), and again 30 min after methylxanthine infusion while still on IRL. IRL resulted in a significant decrease in minute ventilation secondary to a fall in tidal volume. Spontaneously generated transdiaphragmatic pressure increased 7-fold from baseline. EMG activity increased to both segments of the diaphragm. Abdominal expiratory muscle activity was noted after the onset of IRL and was accompanied by a fall in end-expiratory lung volume. The PdiFC was significantly decreased from baseline after 90 min of IRL, demonstrating diaphragmatic fatigue. Aminophylline did not alter the PdiFC of the diaphragm. Diaphragmatic electromyogram and tidal volume increased. No change in diaphragmatic blood flow was demonstrated after infusion of aminophylline. Serum theophylline levels averaged 117 +/- 11 mumol/L (21 +/- 2 micrograms/mL). Caffeine administration did not alter the PdiFC or the diaphragmatic electromyogram during IRL. Blood flow to both segments of the diaphragm decreased after caffeine infusion. Serum caffeine levels averaged 86 +/- 30 mumol/L (16.6 +/- 5.9 micrograms/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Theophylline Poisoning

To the Editor.— We were interested in the report by Shannon and co-workers1 in which they described the use of multiple exchange transfusions for the treatment of an accidental toxic serum theophylline level in an infant in the postoperative phase of an arterial switch procedure. Although we have no problem with the rationale used for an invasive procedure that has multiple complication risks, we would like to emphasize the option for the use of activated charcoal products in infants who are able to tolerate orally administered medications.

Enhancement of Theophylline Clearance by Oral Albuterol

The possible effect of albuterol on theophylline clearance was studied in ten adult volunteers. Subjects received intravenous aminophylline loading dose (5.6 mg/kg), with oral albuterol (4 mg every 6 h), or inhaled albuterol (200 micrograms every 6 h), or alone (control). Theophylline levels were determined for 12-h periods. Theophylline clearance and elimination t 1/2 were calculated. Theophylline clearance was significantly higher when given with oral albuterol, in comparison with control (0.83 +/- 0.05 vs 0.73 +/- 0.06 ml/kg/min, p less than 0.02). Theophylline elimination t 1/2 was shorter with the coadministration of oral albuterol, compared with control (7.1 +/- 0.3 vs. 8.1 +/- 0.6 h, p less than 0.02). These alterations in theophylline clearance and elimination were greater in subjects who had lower control theophylline clearance. Theophylline clearance and elimination t 1/2 recorded with inhaled albuterol were not significantly different from control values. Coadministration of oral albuterol and theophylline resulted in enhancement of theophylline clearance, particularly in subjects with initially slow theophylline elimination. Such patients may require theophylline dosage adjustment as a result of this interaction.

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.

Evaluation of the Vision ® Theophylline assays in the emergency department setting

To determine whether the use of fingerstick blood samples or venipuncture blood samples affect the accuracy and the precision of the Vision Theophylline I assay and the Vision Theophylline II assay in the emergency department setting. Prospective clinical trial. ED in a university teaching hospital. Simultaneous fingerstick and venipuncture blood samples were obtained from adult patients who required baseline theophylline levels in the ED. The Vision system was used in the ED to measure theophylline concentrations from fingerstick and venipuncture samples. Vision samples were drawn and analyzed by one of three pharmacists rounding within the ED between March and October 1990. These pharmacists were instructed by laboratory personnel concerning pertinent operating procedures. The vision Theophylline I and Theophylline II assays are enzyme-inhibitor immunoassays contained within a multi-chamber test packet. The high-performance liquid chromatography (HPLC) theophylline assay was used as the reference method. Linear regression of theophylline concentrations determined by the Vision Theophylline I assay versus HPLC revealed a significant correlation for fingerstick samples (r = .9440; P less than .05) and for venipuncture samples (r = .9750; P less than .05). The accuracy values for Vision Theophylline I assay venipuncture and fingerstick samples versus HPLC were -0.63 +/- 1.2 mg/l and 0.22 +/- 1.8 mg/L, respectively. The precision for Vision Theophylline I assay venipuncture and fingerstick samples versus HPLC were 0.27 and 0.38, respectively. Linear regression of theophylline concentrations determined by the Vision Theophylline II assay versus HPLC revealed a significant correlation for fingerstick samples (r = .9804; P less than .05) and for venipuncture samples (r = .9875; P less than .05). Accuracy values for Vision Theophylline II fingerstick and venipuncture samples versus HPLC were -0.53 +/- 1.4 mg/L and -0.65 +/- 1.3 mg/L, respectively. Precision values for Vision Theophylline II fingerstick and venipuncture samples versus HPLC were 0.34 and 0.29, respectively. There is a strong correlation between theophylline concentrations measured by Vision Theophylline assay versus HPLC, regardless of whether the Vision Theophylline assay is performed on a fingerstick or venipuncture sample. Vision fingerstick samples were more accurate than Vision venipuncture samples for both Vision Theophylline I and II assays. Theophylline concentrations measured by the Vision system using venipuncture samples were slightly more precise than those using fingerstick samples when compared with HPLC analysis. These differences in accuracy and precision were not clinically relevant.

Computer assisted design of a theophylline dosing regimen in acute bronchospasm: Serum concentrations and clinical outcome

The effect of intravenous theophylline on the outcome of inhospital treatment of acute bronchospasm has been assessed, comparing the results achieved by computer-assisted dosing, designed to achieve and maintain a serum theophylline level of 16 micrograms.ml-1 (10 patients) with those of unaided physicians (15 control patients). The outcome measures compared were clinical improvement, peak expiratory flow rate and serum theophylline concentration. Loading doses of theophylline in the control and computer groups were: 167 and 437 mg, respectively. Initial serum theophylline concentrations, measured 20 min after the loading dose, were 13.6 and 17.0 micrograms.ml-1 in the control and computer groups, respectively. In patients who had not received theophylline prior to admission, loading doses and initial concentrations were: 200 mg and 9.4 micrograms.ml-1 in the control group (n = 5) versus 613 mg and 15.7 micrograms.ml-1 in the computer group (n = 4), respectively. During maintenance therapy, serum theophylline concentrations were kept in the therapeutic range (10-20 micrograms.ml-1) throughout 51% and 77% of the hospitalisation period, in the control and computer groups, respectively. There were no differences between the two groups in the rate or extent of clinical improvement or in change in peak expiratory flow rate. The computer assisted theophylline dosing regimen outperformed that of the unaided physicians in achieving and maintaining therapeutic serum theophylline concentrations in acute bronchospasm. There was no correlation between clinical outcome and serum theophylline concentration, but this may have been due to the small sample size and modest difference in serum theophylline between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

A Microassay Method for the Determination of Theophylline in Biological Samples Using HPLC with Electrochemical Detection

Abstract A micro assay method is presented to measure theophylline plasma levels by HPLC with electrochemical detection. Plasma samples of 10 μl were sufficient to determine theophylline levels down to 0.2 μg/ml. Intraday and interday variations were lower than 4% and 6% respectively. This method was evaluated by comparison with an immuno assay and correlation was excellent. The method is sensitive enough to allow blood sampling by the finger prick method in order to perform monitoring of drug levels.

The Effects of Inhaled Albuterol and Oral Theophylline on Gastroesophageal Reflux in Patients With Gastroesophageal Reflux Disease and Obstructive Lung Disease

Patients with gastroesophageal reflux disease may have pulmonary symptoms due to repeated aspiration of gastric contents or reflex bronchospasm during a reflux event. Oral bronchodilators are known to worsen gastroesophageal reflux and may lead to vicious cycle when gastroesophageal reflux causes bronchospasm. The effect of inhaled bronchodilators on gastroesophageal reflux is unknown. We compared the severity of gastroesophageal reflux in patients with documented gastroesophageal reflux disease and obstructive lung disease while they were taking inhaled albuterol or oral theophylline. Nine patients with gastroesophageal reflux disease had 24-hour esophageal pH studies on two separate days approximately 1 week apart. On one study day, the patients received 0.5 mg of albuterol in 2.5 mL of normal saline vias hand-held nebulizer, four times a day. On the other day, the patients received sustained-release theophylline, 200 mg twice a day, or in a dosage taken previously to achieve a serum theophylline level of 55 to 110 mumol/L. The patients had 40% reduction in the total time the pH was less than 4.0 with albuterol than with theophylline (9.7% vs 16.1%). Seven patients had less gastroesophageal reflux while taking albuterol, and two patients had essentially no change. Patients with gastroesophageal reflux disease, who require bronchodilator therapy for obstructive lung disease, have less reflux with inhaled albuterol.

Utilization of Digoxin and Theophylline Assays in the Eastern Province

The utilization of therapeutic drug monitoring (TDM) for serum digoxin and theophylline was assessed with respect to the indication, time of sample collection and contribution to patient care. A total of 585 serum drug level determinations of digoxin (275) and theophylline (328) were done in a four month period. Reasons for requests were subtherapeutic response (27.5%), suspected toxicity (3.8%), baseline data (26.7%), patients at risk for toxicity (7.7%), and for the remaining 34.4% of orders, no reason was stated. The highest number of requests 246 (42.1%) were from the inpatient ward (INP), followed by emergency room (ER) 32.6%, outpatient department (OPD) 13% and intensive care unit (ICU) 12.3%. Repeated assays accounted for 363 determinations of which 55.9% had levels similar to the previous ones. In this study, we found a high incidence of inappropriateness in patient selection (34.4%), time of serum sample collection (28.4%), and dosage adjustment (46.8%). However, when these audit criteria were analyzed together, the overall appropriateness was as low as 33.5%. This indicated that serum drug monitoring was poorly utilized and did not contribute much to the patient's care. This results in an estimated financial loss per year (for inappropriate use of digoxin and theophylline levels) of about 37,344 Saudi Riyals (US $9,956.00). Corrective educational programs for the staff, based on standard guidelines for TDM, have been initiated and this study is a baseline for future prospective audits.

Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease

Elevation of serum theophylline levels by ipriflavone in a patient with chronic obstructive pulmonary disease

Relationship between serum and saliva theophylline levels in patients with cystic fibrosis.

Theophylline levels in stimulated and unstimulated mixed saliva were compared with total and free (unbound) serum theophylline levels in 11 outpatients with cystic fibrosis (CF) who were using theophylline regularly. Stimulated saliva from CF patients predicted both total and unbound serum theophylline concentrations to within +/- 1 microgram/ml in 53.3 and 80.0%, respectively, of the samples examined. In addition, the total serum levels from CF patients could be used to predict unbound serum concentrations to within +/- 1 micrograms/ml in 100% of the cases examined. Furthermore, it was observed that prediction equations derived in a previous study with asthmatics employing identical methodology would allow both unbound and total serum theophylline levels to be predicted from saliva levels in CF patients with a degree of accuracy and precision that was approximately equal to or slightly better than the results obtained using prediction equations derived in other CF patients. These results indicate that saliva levels allow predictions of the unbound serum theophylline levels with greater accuracy and precision than they predict total serum theophylline levels. In addition, total serum levels can be used to reliably predict unbound serum levels. The use of mixed stimulated saliva is recommended as a reliable noninvasive method for monitoring unbound serum theophylline levels. The therapeutic range for saliva, which corresponds to the accepted total serum concentration range of 10-20 micrograms/ml, is approximately 5.55-11.3 micrograms/ml.

Hepatic function after porto-systemic shunt

Advanced hepatic injury can be identified by the appearance of jaundice, coagulopathy, or encephalopathy but these conditions are late, irreversible findings and represent the end stage of a long insidious process. Currently available methods for assessing “liver function” (SGOT, SGPT, GGT, LDH, etc.) do not actually measure liver function. In this study we prospectively evaluated “true” liver function in patients undergoing porto-systemic shunt. Effective hepatic blood flow [low dose galactose clearance (EHBF)], hepatocyte transport (theophylline levels at 24 hr), and hepatic conjugation ability [acetaminophen metabolism to its glucuronide and sulfate conjugates ((S + G)/A) and acetaminophen remaining at 24 hr (A24)] were measured in normal males (NL) and in patients pre- and post-8-mm H-graft portacaval shunt (PCS). All data are means ± SEM, analyzed by Student's t test, and significance was accepted if P < 0.05. There were no significant differences in EHBF even after PCS. Hepatocyte transport was decreased in pre-op (1.43 ± 0.16 vs 0.74 ± 0.08) and post-op (1.79 ± 0.34) PCS patients. Hepatic conjugating ability was also decreased in pre-op PCS patients [A24 was increased (0.24 ± 0.11 vs 0.01 ± 0.01) while the ratio of conjugation products to acetaminophen remained the same]. The ability of the liver to conjugate substrate was severely compromised postoperatively [A24 − 1.27 ± 0.67, (S + G)/A − 1.19 ± 0.34]. We believe that changes in liver function can be accurately measured using these noninvasive methods, and in using these methods we have identified altered hepatocyte transport and conjugating ability in patients undergoing porto-systemic shunt surgery.

Effectiveness and side effects of two different doses of caffeine in preventing apnea in premature infants.

The effectiveness of caffeine citrate in preventing idiopathic apnea in premature infants was evaluated. Thirty-seven preterm infants born before the 32nd week of gestation were studied. After an intravenous loading dose of 10 mg/kg of caffeine citrate, two different oral maintenance regimens were followed: 5 mg/kg in Group I and 2.5 mg/kg in Group II. A significant decrease in the number of apneic spells occurred in both treated groups as compared with a control group. In Group II, the frequency of side effects such as tachycardia and gastrointestinal intolerance was significantly lower than in Group I. Group II theophylline plasma levels were significantly lower than those of Group I. The lower Group II theophylline levels presumably explain the reduced frequency of side effects.

Bronchodilator intake and plasma levels on admission for severe acute asthma

We have measured the plasma levels of salbutamol, terbutaline and theophylline in 140 patients (70 men, mean age 57 yrs) arriving for emergency treatment with severe acute asthma. The aim of the study was to investigate how the measured plasma levels correlated with the reported bronchodilator intake and whether the pretreatment beta 2-agonist levels influenced the effect of emergency salbutamol treatment. We found a highly significant correlation between the reported 24 h dose and the measured plasma concentrations for all three drugs. A plasma concentration less than 40 mumol.l-1 was found in 63 of the 107 patients who had taken theophylline, while no patient had a plasma concentration greater than 110 mumol.l-1. A plasma concentration above the suggested therapeutic range was found in 23 of the 95 patients who had taken terbutaline (greater than 30 nmol.l-1) and in 12 of the 98 patients who had taken salbutamol (greater than 60 nmol.l-1). A significant negative correlation was found between the initial plasma beta 2-agonist levels and the bronchodilation after i.v. salbutamol treatment (5 micrograms.kg-1), while there was no clear indication that high plasma beta 2-agonist levels reduced the bronchodilator effect of a high dose of inhaled salbutamol (0.15 mg.kg-1 x 2). We conclude that some patients arriving with acute asthma have high blood concentrations of beta 2-agonists, which possibly limit the response to i.v. beta 2-agonist treatment, while the effect of high-dose inhaled beta 2-agonists appears to be related to a lesser degree to the drug concentration on arrival. In this study overtreatment with theophylline appears to be uncommon.

Regulation of annexin I in adipogenesis: cAMP-independent action of methylisobutylxanthine.

The differentiation of 3T3-L1 fibroblasts to adipocytes can be accelerated by the addition of 1-methyl-3-isobutylxanthine (MIX), insulin, and dexamethasone to the culture medium. During differentiation, we have demonstrated that the level of both annexin I mRNA and protein decreases. The half-times for this reduction were 2 h and 10 h for annexin I mRNA and protein, respectively. Of the added agents in the differentiation medium, only MIX caused a decline in annexin I expression in 3T3-L1 fibroblasts. The MIX effect in fibroblasts was reversible and required de novo transcription but not protein synthesis. Although MIX could be replaced by high levels of theophylline, neither agonists of the beta-adrenergic receptor nor intracellular second messengers, cAMP and cGMP, were able to reduce annexin I. The potential role of annexin I in cellular differentiation is discussed.

Effects of enoxacin and ciprofloxacin on the theophylline metabolism in humans.

Some kinds of newer fluoroquinolone antibiotics are known to interact with theophylline, which is widely used as a potent bronchodilator in asthma or chronic obstructive lung disease. To evaluate the effect of enoxacin and ciprofloxacin on the metabolism of theophylline, aminophylline was administered intravenously in bolus (6 mg/kg) over 30 minutes to 6 healthy volunteers (age: year, body weight: , height: , female 3, male 3) before and after per oral 5-day medication of enoxacin and ciprofloxacin, respectively and we measured the level of theophylline in serum. The results were as follows: 1) Enoxacin and ciprofloxacin did not influence the volume of distribution significantly. 2) Enoxacin decreased the clearance of theophylline significantly (from to : p: p>0.005). 3) Enoxacin increased the elimination half life of theophylline significantly (from to : p: p>0.05). These results suggested that enoxacin influenced clearance and elimination half life significantly and thorough monitoring of the level of theophylline in patients with coadminstration of enoxacin and theophylline was necessary. In case of ciprofloxacin, the influence on the metabolism of theophylline was not statistically significant, but one exceptionally large decrease of the clearance and increase of the elimination halflife of theophylline suggested the necessity of monitoring of theophylline level during coadministration of ciprofloxacin and theophylline.