Serum Theophylline Research Articles

Lack of a Pharmacokinetic Interaction between Doxapram and Theophylline in Apnea of Prematurity

To examine the possibility of a pharmacokinetic interaction between doxapram and theophylline, both drugs (1.5 mg/kg/h doxapram, and 0.5 mg/kg/h theophylline) were administered in that order and in reverse order to patients with apnea of prematurity. During the therapeutic steady state phase of doxapram considerable serum theophylline concentrations were found despite discontinuation of the latter drug for at least 48 h. Serum doxapram concentrations during theophylline steady state were negligible. Pretreatments of theophylline failed to alter the pharmacokinetic indices of doxapram. Thus, a lack of pharmacokinetic interaction between the two drugs was demonstrated.

Toxic Interaction Between Fluvoxamine and Sustained Release Theophylline in an 11-Year-Old Boy

An 11-year-old boy with asthma had been receiving a controlled release theophylline preparation. He was prescribed fluvoxamine for a depressive disorder and within a week complained of severe headaches, tiredness and vomiting. His serum theophylline concentration had increased from 14.2 mg/L (shortly before fluvoxamine was started) to 27.4 mg/L. Fluvoxamine was withdrawn and theophylline concentrations decreased. Clomipramine was substituted for fluvoxamine with no further problems, and a later theophylline concentration was 13.7 mg/L. Competitive inhibition of hepatic microsomal enzymes by fluvoxamine may have been responsible for the elevated theophylline concentrations and toxicity observed in this case.

Aminophylline in the Outpatient Management of Decompensated Chronic Obstructive Pulmonary Disease

The objective of this study was to determine if IV aminophylline reduces the risk of relapse after treatment of decompensated COPD in an ED. Forty-six visits in which IV aminophylline was given (T visits) were compared with an equal number of visits in which it was withheld (N visits) with respect to pretreatment serum theophylline level, number of treatments with nebulized bronchodilators and use of parenteral beta-adrenergic drugs, IV corticosteroids and prednisone. The difference in 48-h relapse rates for T and N visits was examined by McNemar's test. No differences were found between T and N visits with respect to vital signs, pretreatment FEV1, arterial blood gas values, hematocrit level or blood leukocyte count. The 48-h relapse rate for T visits (22.2 percent) was significantly higher than for N visits (6.7 percent; p = 0.035). Aminophylline does not appear to be beneficial for outpatients with decompensated COPD and may be harmful.

Inhaled Albuterol and Oral Prednisone Therapy in Hospitalized Adult Asthmatics: Does Aminophylline Add Any Benefit?

To determine the efficacy of intravenous aminophylline in the treatment of adult patients hospitalized for exacerbation of asthma.Randomized, double-blind, placebo-controlled trial throughout the study.University Hospital Clinical Research Center.Forty-four patients admitted from the emergency room with a primary diagnosis asthma; 39 patients completed the study.Patients received either intravenous aminophylline or placebo in addition to frequent nebulized albuterol; prednisone 0.5 mg/kg body weight every 6 h orally; and supplemental oxygen. Aminophylline infusion rates were adjusted to achieve serum theophylline concentrations of 10 to 20 micrograms/ml. Changes were made in placebo infusion rates to maintain the double blind design.Forced expiratory volume in 1 s (FEV1) and other spirometric measurements every 8 h by a blinded investigator or trained respiratory therapist. Subjective patient response and duration of hospitalization were compared. No difference in spirometric measurements was observed between the two groups at any time point. On admission to the study, FEV1 in the placebo group was 41.5 (+/- 2.9) percent predicted and in the aminophylline group 34.7 (+/- 2.3) percent predicted (p = 0.08). At discharge, FEV1 was 70.4 (+/- 2.9) percent predicted in the placebo group and 63.7 (+/- 2.8) percent predicted in the theophylline group (p = 0.10). There was no difference in subjective patient rating or duration of hospitalization between the two groups (placebo 1.95 days and aminophylline 1.78 days, p = 0.51).Our results suggest that aminophylline therapy does not add significant benefit to other standard therapies in hospitalized adult asthmatic patients. Because of the risks and cost of aminophylline treatment in the hospital setting, further research is needed to determine if there are subgroups of adult asthmatics who may benefit from the addition of aminophylline to other standard optimal therapies.

Estimation of Theophylline Clearance During Continuous Arteriovenous Hemofiltration

Pharmacologic agents and other non-protein-bound compounds smaller than 5,000 daltons have the potential to be removed by continuous arteriovenous hemofiltration (CAVH). A proposed method for estimating drug clearance by CAVH (ClCAVH) equates ultrafiltrate clearance to the product of the sieving coefficient and the average ultrafiltration rate. This simplified approach for estimating ClCAVH would be a clinically useful method for calculating replacement doses, as it economizes on the sampling and analytical requirements associated with the conventional method. Presented are some theoretical considerations and a brief evaluation of the accuracy of this proposed method. The evaluation was conducted using an animal model whereby CAVH was performed in four male beagles. During the hemofiltration period, an i.v. bolus of theophylline, 6 mg/kg, was administered over 15 s. Samples for analysis of theophylline were collected from the arterial, venous, and ultrafiltrate ports at 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, 360, and 480 min following dosage administration. The volume of ultrafiltrate produced during each collection interval was measured. Theophylline serum concentrations were determined by a high performance liquid chromatography assay. Statistically, the simplified method was found to result in significantly (p less than 0.05) larger estimates of ultrafiltrate clearance when compared to the conventional method. However, the average magnitude of difference was only 9% and does not constitute a clinically significant margin between the two methods.

Evaluation of the Acculevel Theophylline Assay

Abstract As a quality assurance study, we evaluated the rapid on-site AccuLevel theophylline assay and compared the results to the reference method of High Performance Liquid Chromatography (HPLC). The rapid result was needed in order to provide more timely treatment for patients presented to the Emergency Medical Department (EMD) who required a quantitative serum theophylline determination early in the course of treatment. A good correlation between the theophylline concentrations simultaneously determined by AccuLevel and HPLC was observed; r2 =0.916, n=96. A slight positive bias by AccuLevel was noted with the mean of concentrations being 11.7 mg/L and 13.2 mg/L for HPLC and AccuLevel, respectively. Precision of the assay was found to be 4.6%. Because of the delay in transporting specimens from the EMD to the Clinical Laboratories at our Medical Center, the EMD was able to obtain quantitative theophylline serum values from 30 minutes to 1.5 hours sooner by using the AccuLevel, on-site test.

The Influence of Age vs Peak Serum Concentration on Life-Threatening Events After Chronic Theophylline Intoxication

To identify risk factors for the development of seizures and cardiac arrhythmias after chronic, unintentional theophylline intoxication we monitored the clinical course of 72 consecutive patients referred to a regional poison center with chronic theophylline intoxication (serum theophylline concentration, greater than or equal to 167 mumol/L after protracted use). The median age of the sample was 47.5 years (range, 4 days to 91 years). Median peak theophylline concentration was 239 mumol/L, with a range of 167 to 722 mumol/L. A life-threatening event (LTE) occurred in 28 patients (39%) that included seizures in eight and a major cardiac arrhythmia in 22. The median peak (theophylline) of patients who had an LTE vs those who did not was 235.8 vs 238.7 mumol/L. However, the median age of patients with an LTE compared with those without an LTE was significantly greater (70.5 vs 18.0 years). Stratification of data by chronologic age revealed a stepwise increase in the frequency of LTE with advancing years: patients more than 75 years old had a 16.7-fold greater risk of LTE than patients less than 25 years old (95% confidence interval, 3.56, 77.5) despite comparable intergroup median serum (theophylline). These data suggest the primary determinant of LTEs after chronic theophylline intoxication is chronologic age. Elderly patients have an inordinately greater risk of LTE than younger patients. Peak serum theophylline concentration cannot predict which patients with chronic theophylline intoxication will have an LTE. Finally, these data indicate that theophylline should be used cautiously and with frequent monitoring of serum theophylline concentrations in elderly patients.

Comparison of Unbound and Total Serum Theophylline Concentrations with Those of Stimulated and Unstimulated Saliva in Asthmatic Children

Unstimulated saliva, citric acid stimulated saliva, and serum were collected from 31 asthmatic children taking theophylline. Salivary theophylline concentrations, and total and unbound serum theophylline concentrations were measured. The correlation coefficients between both types of saliva, and total and unbound serum theophylline were all statistically significant (p less than 0.001). The highest correlation coefficients were obtained with stimulated saliva and total serum concentrations (r = 0.98), and stimulated saliva and unbound serum (r = 0.96). The coefficients when unstimulated saliva was compared to either total or unbound serum concentrations were 0.90 and 0.89, respectively. Serum binding of theophylline averaged 58.1%. Unstimulated saliva had a higher mean theophylline concentration than stimulated saliva. The results suggest that salivary monitoring using stimulated saliva may be used to predict serum concentrations with a high degree of confidence when the saliva levels are substantially lower than, higher than, or in the middle of the therapeutic range, but there is a considerable degree of uncertainty when the salivary values are near the lower or upper end of the therapeutic range.

Predictability and intraindividual variability of serum theophylline concentrations in patients with obstructive lung disease: 12-h versus 24-h dosing

The predictability and intraindividual variability of serum theophylline concentrations (STC) after different dosing schedules were investigated in 24 patients with chronic obstructive lung disease (COLD). Three oral regimens were compared in 3 groups of 8 randomly assigned patients. Group I:Drug A once daily in the evening; Group II: Drug A b.d.; Group III: Drug B b.d. The doses for each patient were estimated by Bayesian forecasting aiming at an STC of 10-15 mg/l. STC and FEV1 were measured on two consecutive days at steady-state. The day-to-day variability of STC was less than 20% in all three groups. The within-day fluctuation in Group I amounted to 259% (median) compared to 57% and 38% in Groups II and III, respectively. Dose adjustment by Bayesian forecasting resulted in a therapeutic STC in most patients with a b.d. regimen, whereas for the once daily dose the prediction was not satisfactory. No difference in lung function was found between the 24-h and 12-h dosing, probably because of the large intersubject variability in FEV1. Therefore, the question whether the differences in STC profile are of clinical importance in COLD can only be investigated in a larger group of patients.

Theophylline poisoning—a review of 64 cases

Sixty-four cases of theophylline poisoning were reviewed. All but two cases represented international self poisoning. The majority of patients were young females who presented acutely after ingestion of sustained release preparations prescribed for asthma. Serum theophylline levels (mean 365 mumol/l, SD 177) indicated a high risk of toxicity. Electrolyte and metabolic abnormalities (hypokalaemia, hypomagnesaemia, hypophosphataemia, hyperglycaemia, acid-base disturbances and leucocytosis) were common. Serum potassium, serum glucose, leucocyte count and length of stay in the intensive care unit all correlated strongly with maximum serum theophylline level (p less than 0.001). The low incidence of life-threatening manifestations of severe toxicity (hypotension, serious arrhythmias or seizures) and excellent outcome, contrasts with many previous reports. The results support the use of a management regimen which emphasizes intensive supportive therapy and restricts the use of charcoal haemoperfusion.

Cardiac Arrhythmias during Theophylline Toxicity: A Prospective Continuous Electrocardiographic Study

To examine the effects of theophylline toxicity on cardiac rhythm, patients underwent continuous ambulatory ECG recording during acute theophylline toxicity and recovery. The patients, who were recruited form inpatient wards, intensive care units, and emergency departments of a University Medical Center and a Veterans Administration Medical Center, had serum theophylline concentrations (STC) greater than 30 mg/L. There were 14 men and two women with a mean age of 66 years. Fourteen patients had COPD and developed toxicity following long-term theophylline overmedication. Two patients had asthma and ingested an intentional overdose. The STC at the onset of ECG recording ranged from 23 to 67 mg/L. The principal rhythm was sinus in 15 patients; one patient had atrial fibrillation. Sinus tachycardia (heart rate greater than 100/min) was common, and heart rate fell in proportion to STC as toxicity resolved. Supraventricular ectopic beats (SVEs) were noted in seven patients with multiple runs of SVE being present in four. One patient developed multifocal atrial tachycardia (MAT) during toxicity that resolved spontaneously. During the 11 +/- 8 hours of recording during toxicity (STC greater than 20 mg/L), 80 percent of patients had ventricular premature beats (VPBs), 44 percent had paired VPBs, and 25 percent had ventricular runs. One elderly patient with heart disease developed sustained ventricular tachycardia (VT) when STC = 66 mg/L. No other patient had ventricular ectopy that required intervention. During the 10 +/- 6 hours of recording during the "recovery phase" (STC less than 20 mg/L), all patients with VPBs continued to have ectopy; however, the number of VPBs declined significantly. A follow-up 24-hour ECG recording obtained one week after recovery from toxicity in the patient with sustained VT demonstrated marked reduction in the frequency and complexity of VPBs. Patients with frequent (greater than 10/h) or repetitive VPBs were older (p less than 0.05) than those without complex ectopy. There was a trend (p = 0.07) suggesting patients with underlying heart disease were at risk for having complex ventricular ectopy. We conclude that sinus tachycardia, SVE, and VPBs are common among patients with theophylline toxicity; however, sustained ventricular or supraventricular tachyarrhythmias that require antiarrhythmic therapy are uncommon.

Update on Quinolone Drug Interactions: Sucralfate, theophylline, and antacids can affect the bioavailability of quinolones.

Concurrent administration of both ciprofloxacin and norfloxacin with sucralfate leads to a decrease in quinolone bioavailability. It is unknown whether this decrease is clinically significant because studies have focused primarily on pharmacokinetics and not therapeutic outcomes. A reasonable recommendation may be to avoid using sucralfate and norfloxacin concurrently, or avoid administration of norfloxacin and ciprofloxacin within two hours of sucralfate administration. Magnesium- and aluminum-containing antacids may also interfere with quinolone absorption. Calcium carbonate and H2 receptor antagonists do not appear to interact with quinolones and may be considered as an alternative to sucralfate or magnesium- and aluminum-containing antacids when quinolones are administered. Concurrent administration of ciprofloxacin and theophylline may precipitate theophylline toxicity if not monitored carefully. Some clinicians recommend a 30% empiric reduction in theophylline dosage when ciprofloxacin therapy is initiated. Because the drug interaction is not completely predictable, the patient's theophylline levels should be monitored and signs and symptoms of toxicity noted, adjusting the dose as needed. Decreased theophylline clearance may persist for as long as five days following discontinuation of ciprofloxacin. Some potential for slight increases in serum theophylline concentrations secondary to norfloxacin administration may exist. However, it is unlikely to be clinically significant, based on currently available information.

Effect of Aminophylline on Diaphragmatic Contractility in the Piglet

Minute ventilation, arterial blood gases, arterial pH, cardiac output, and transdiaphragmatic force generation, both during spontaneous ventilation and in response to phrenic nerve stimulation during airway occlusion at end expiration, were measured in nine anesthetized, tracheostomized piglets before and 30 min after parenteral infusion of 20 mg/kg aminophylline. Serum theophylline levels averaged 109 +/- 21 mumol/L (19.7 +/- 3.7 micrograms/mL) at 30 min postinfusion. No significant changes were noted in pH, blood gases, blood pressure, or ventilatory measures after aminophylline. Aminophylline infusion also had no effect on transdiaphragmatic force generation at any frequency of phrenic nerve stimulation studied. It is concluded that aminophylline has no effect on diaphragmatic contractility in the quietly breathing, nonfatigued piglet.

Twenty-four Hour Lung Function in Adult Patients with Asthma: Chronoptimized Theophylline Therapy Once-daily Dosing in the Evening versus Conventional Twice-daily Dosing

Many patients with asthma experience a worsening of symptoms at night and in the early morning, resulting in sleep disruption and possibly altered daily performance. A bronchodilator agent that exerts its maximal effect overnight to control nocturnal symptoms, without a worsening of the disease during the daytime, should improve the treatment of asthma. This investigation examined the efficacy and kinetics of a new chronotherapeutically optimized, sustained-release theophylline formulation administered once daily (OD) in the evening at 8:00 P.M. in comparison with a conventional sustained-release theophylline administered twice daily (TD) at 8:00 A.M. and at 8:00 P.M. in the same dose. After a theophylline clearance study to substantiate normal or slow metabolism of the drug, a dose-titration period, and a 24-h baseline spirometric study of patients not receiving any medication, participants were randomized to 7-day treatment phases with either OD or TD. Each outpatient segment of 6 days of OD and TD was followed by a 24-h inpatient study on Day 7 when serum drug level and spirometric (PEF, FEV1, and FEF25-75) parameters were obtained every 2 h. The conventional TD treatment was associated with a constant serum theophylline level over the 24 h. In contrast, the OD treatment was associated with larger peak-to-trough drug level fluctuation, with higher levels produced overnight and lower ones in the evening at the end of the dosing interval. Compared with the baseline references, both OD and TD significantly improved airflow over the entire 24 h and to a comparable extent. However, between 2:00 and 6:00 A.M., PEF and FEV1 were significantly greater with OD than with TD. The improvement in PEF and FEV1 at this time, because of OD, was correlated with the serum theophylline level. This was not the case for TD. The improvement in airflow over baseline values between 2:00 and 6:00 P.M. was not correlated with theophylline level with either treatment regime. Overall, the chronotherapeutically conceptualized OD treatment administered in the evening resulted in better airflow levels overnight than did the TD regime without loss of airflow in the afternoon.

Theophylline concentrations in patients with acute exacerbation of COPD

Patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) frequently report a history of theophylline use prior to arrival in the emergency department. The reliability of using this history to guide aminophylline therapy is, however, unclear. The authors studied patients with an acute exacerbation of COPD to determine the relation between the initial theophylline level and the medication history. Seventy-nine patients with a mean age of 64.3 years were entered into the study. The average theophylline level was 10.8 μg/mL. Forty-seven percent of the patients had subtherapeutic levels, 46% had therapeutic levels, and 7% had toxic levels. There were weak although statistically significant correlations between the theophylline level and the interval since the last theophylline dose ( r=−.40, P<.001), as well as with the last recorded outpatient theophylline level ( r=.45, P<.001). However, the theophylline level could not be predicted accurately in a number of patients. The authors conclude, because the prediction rule was often inaccurate, aminophylline therapy in patients with acute exacerbation of COPD should be based on direct measurement of the serum theophylline level.

A Rapid and Specific High-Performance Liquid Chromatographic Assay for Theophylline in Biological Fluids

A rapid, specific high-performance liquid chromatographic analysis of theophylline in plasma, serum, and saliva is described. Proteins present in the biological samples are precipitated with 6% perchloric acid and the clear supernatant is chromatographed on a reversed-phase column. Only 100 microL of serum is required and concentrations as low as 0.07 micrograms/mL can be measured accurately. Other xanthines do not interfere in the assay. Within- and between-day variation is less than or equal to 2.2%. The method shows less bias and greater precision than the TDx (Abbott Diagnostics) procedure commonly used in clinical laboratories.

Theophylline toxicity: Clinical features of 116 consecutive cases

purpose: To examine the predisposing factors, clinical and laboratory characteristics, management, course, and outcome of consecutive cases of theophylline toxicity in an outpatient setting. patients and methods: Toxicology records and hospital charts of consecutive patients with a serum theophylline concentration (STC) greater than 30 mg/L (167 μmol/L) identified in the emergency departments (EDS) of a University Medical Center and a Veterans Administration Medical Center were reviewed. results: Ten percent and 2.8% of 5,557 consecutive STCs measured in the EDs over 2 years were greater than 20 mg/L (111 μmol/L) and greater than 30 mg/L (167 μmol/L), respectively. One hundred sixteen cases with STC greater than 30 mg/L were identified. Fourteen (12%) and 102 (88%) were due to acute overdose and chronic overmedication, respectively. Principal predisposing factors included patient and/or physician dosing errors and conditions or medications that reduce theophylline clearance. One or more toxic manifestations were present in 109 (94%) cases. Fifty percent of patients had mild toxicity, 38% had moderate toxicity, and 7% had severe or life-threatening toxicity. Seven (6%) patients died when STC was still in the toxic range and/or as a result of toxicity. Acute overdose was associated with higher peak STC (p <0.001), younger age (p <0.01), and greater mortality (p <0.05) than chronic overmedication. Peak STC correlated significantly with the severity of toxicity for patients with acute overdose (p <0.01) but not for patients with chronic overmedication. All three patients with acute overdose and fatal toxicity had peak STCs greater than 100 mg/L (555 μmol/L) and fulminant toxicity, whereas the four patients with chronic overmedication who died during toxicity had peak STCs in the 40 to 60 mg/L (222 to 333 μmol/L) range and most died of respiratory failure rather than directly from toxicity. Patients with acute overdose who had the delayed onset of severe or life-threatening toxicity and/or died from toxicity were accurately identified using previously published criteria for prophylactic charcoal hemoperfusion. In contrast, the predictive value of the criteria applied to patients with chronic overmedication was poor. Two patients with acute overdose underwent charcoal hemoperfusion, but died. No patient with chronic overmedication received charcoal hemoperfusion. conclusion: Toxic-range STCs are relatively common in the ED population, occur primarily as a result of patient and physician dosing errors, and cause a broad range of toxic manifestations of varying severity. Peak STC correlates with the severity of toxicity and outcome for acute overdose but not chronic overmedication intoxication. Previously published criteria for prophylactic charcoal hemoperfusion accurately identify patients with acute overdose but not patients with chronic overmedication at risk for serious complications and death.

Serum theophylline analysis by isotope dilution mass spectrometry

Serum theophylline analysis was attempted using stable isotope dilution mass spectrometry. Theophylline 15N-labelled in position 7 was used as internal standard. The analysis was performed at resolution 3000 by selected ion monitoring with temperature programming. The sample was introduced in underivatized form by means of the direct inlet probe. Good linearity was obtained in the concentration range 5-40 micrograms ml-1 with relative standard deviations less than 6%. The method is simple and permits six samples to be run per hour. Sensitivity permits analysis at 0.5 micrograms ml-1 at a signal to noise ratio 4:1.

Seizure with Ciprofloxacin and Theophylline Combined Therapy

Ciprofloxacin has been reported to cause theophylline toxicity by inhibiting theophylline metabolism. A 93-year-old woman without a known seizure history, while on ciprofloxacin and theophylline combined therapy, experienced a grand mal seizure. Her serum theophylline concentration at the time was 20 micrograms/mL. On previous occasion of theophylline toxicity, she had a serum theophylline concentration of 27 micrograms/ml but the patient did not experience any seizure. Several reports suggest that the combination of theophylline and ciprofloxacin has an additive inhibitory effect on gamma-aminobutyric acid (GABA) sites. Inhibition of the binding of GABA to its receptor sites has been related to the convulsant effects of other drugs. The seizure in our patient may have been caused by altered pharmacokinetics and pharmacodynamics brought about by combined therapy of theophylline and ciprofloxacin.

Prediction of serum theophylline concentration after acute theophylline intoxication

Prediction of serum theophylline concentration after acute theophylline intoxication