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At least 19 recordsLinked to original sources
PubMed1981

Comparative absorption of theophylline from theophylline-guaifenesin tablets and liquid and from a reference theophylline liquid.

This single-dose, three-way crossover study in 18 healthy adults compared the oral absorption of theophylline from a theophylline-guaifenesin tablet and from a theophylline-guaifenesin liquid with absorption from a theophylline liquid. Each dose form contained 500 mg theophylline and, when indicated, 400 mg guaifenesin. The extents of theophylline absorption from the formulations were within 10% of each other. The absolute differences in the areas under the curve among the formulations were small and, although significantly higher statistically for the theophylline-guaifenesin tablet, are without therapeutic consequence. The theophylline plasma level curves from each of the three formulations were similar. Comparable theophylline absorption and elimination characteristics were seen.

Adult↗
PubMedDate not supplied

Serum theophylline profile with once-daily theophylline (Uniphyl) following conversion from intravenous theophylline in adult asthmatic patients.

Although guidelines are available for conversion from intravenous (IV) theophylline to twice-daily, oral, controlled-release theophylline, the optimal method for conversion to Uniphyl, a chronotherapeutically formulated, once-daily theophylline preparation, has not been previously evaluated. The present study was designed to prospectively evaluate a method for converting patients from IV theophylline to Uniphyl, to formulate simple, practical dosage recommendations for use in clinical practice. Ten patients with acute exacerbation of asthma receiving IV theophylline for > or = 48 hours and with steady state serum theophylline concentrations (STCs) between 4.5 and 15.5 mg/L (25 and 86 mumol/L) were enrolled into the study. Patients with STCs > or = 4.5 and < 12 mg/L (> or = 25 and < 66 mumol/L) and those with STCs > or = 12 and < or = 15.5 mg/L (> or = 66 and < or = 86 mumol/L) received their first Uniphyl dose immediately following termination of IV theophylline (No Time Lapse [NTL] group) and after a 4-hour delay (Time Lapse [TL] group), respectively. The differences in the area under the curve values between Uniphyl dosing and IV theophylline were 11% in the NTL group (1214.6 +/- 247.9 mumol/h.L-1 vs 1370.4 +/- 148.1 mumol/h.L-1, 95% confidence interval, 74% to 103%; P = 0.068) and 10% in the TL group (1959.4 +/- 165.1 mumol/h.L-1 vs 1784.6 +/- 119.4 mumol/h.L-1, 95% confidence interval, 103% to 117%; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1977

Theophylline bioavailability: a comparison of the oral absorption of a theophylline elixir and two combination theophylline tablets to intravenous aminophylline.

The bioavailability of theophylline from single doses of an elixir (Elixophyllin) and two different tablet formulations, as compared to intravenous aminophylline, was studied with a crossover design in 12 normal volunteers. Both tablet formulations (Marax and Tedral) contain ephedrine. Marax contains hydroxyzine hydrochloride, and Tedral contains phenobarbital. The absorption of theophylline was most rapid from the elixir, whereas that from Marax was faster than that from Tedral. The peak concentrations of theophylline after administration of the 3 oral dosage forms were in the order, elixir greater than Marax greater than Tedral, however, the time to achieve peak concentration was highly variable and did not differ significantly among the 3 products. On the basis of area under the serum concentration-time curves, the absorption of theophylline from the elixir and from Marax was essentially complete. The area under the serum concentration curve after administration of Tedral was significantly less than that after intravenous aminophylline, elixir, and Marax; however, when the individual areas under the concentration curves were adjusted for intrasubject variation in elimination rate constant, the mean area under the concentration curve after Tedral no longer differed significantly from those of the intravenous and other two oral products. A large degree of intersubject variation in the oral absorption of theophylline was observe din this study. Therefore, in addition to the well-documented, large individual variation in the serum clearance of theophylline, intersubject differences in the absorption of the drug is another factor that complicates proper adjustment of the dose in oral theophylline therapy.

Administration, Oral↗
PubMed1992

Inhibitory effect of theophylline, theophylline-7-acetic acid, ambroxol and ambroxol-theophylline-7-acetate on rat lung cAMP phosphodiesterase isoenzymes.

It is assumed that theophylline (THEO) and its xanthinic derivatives inhibit lung phosphodiesterase (PDE) and block adenosine receptors in the induction of bronchodilatation. Since the theophyllinic compound ambroxol-theophylline-7-acetic acid (ATA) has been shown in vivo to be a sound bronchodilator, this paper compares the action of ambroxol-theophylline-7-acetate (ATA), its two components, theophylline-7-acetic acid (TAA) and ambroxol (AMB), and theophylline (THEO) on the hydrolytic activity of three rat-lung cAMP PDE (types I, III and IV) and on striatal adenosine receptors. THEO inhibited all three isoenzymes with equal intensity, whereas ATA was as powerful but inhibited types III and IV only, on which AMB and TAA also showed lower effects. Lastly, unlike THEO, ATA and its two components were unable to antagonize adenosine receptors. Taken as a whole, these results suggest that the bronchodilating activity of ATA is the result of specific inhibition of particular forms of PDE and is thus more specific than that of THEO alone.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Plasma theophylline and caffeine and plasma clearance of theophylline during theophylline treatment in the first year of life.

Plasma concentrations of caffeine and theophylline were simultaneously determined in 17 preterm infants after oral administration of aminophylline for treatment of apnoea. The ratio of caffeine/theophylline concentration in plasma increased during the first 2 weeks of treatment, owing to the longer time required for caffeine than for theophylline to reach steady state. The caffeine/theophylline ratio at steady state was 0.57 +/- 0.03 (mean +/- SE). Thus, caffeine contributed significantly to the total methylxanthine load in the infants. The plasma clearance of theophylline was calculated from the plasma steady state concentrations. In 3 preterm infants treated with oral aminophylline, repeated sampling showed an approximately linear increase in clearance with time from 16.8 +/- 0.4 (mean +/- SE) at a postnatal age of 6-11 days to 30.9 +/- 2.5 ml/kg/h at 64-69 days. In 1 full-term infant treated with oral theophylline from 3.5 to 11.5 months of age, the plasma clearance of theophylline increased in a roughly linear manner, reaching a plateau of about 100 ml/kg/h at 6-7 months of age. This corresponds to the clearance found in 1-4 year old infants.

Apnea↗
PubMed2000

Long acting beta-agonists versus theophylline for maintenance treatment of asthma.

BACKGROUND: Theophylline and long acting beta2-agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. OBJECTIVES: To assess the comparative efficacy, safety and side-effects of long-acting beta-agonists and theophylline in the maintenance treatment of asthma. SEARCH STRATEGY: Randomised, controlled trials (RCTs) were identified using the Cochrane Airways Group register. The register was searched using the following terms: asthma and theophylline and long acting beta-agonist or formoterol or foradile or eformoterol or salmeterol or bambuterol or bitolterol. Titles and abstracts were then screened to identify potentially relevant studies. The bibliography of each RCT was searched for additional RCTs. Authors of identified RCTs were contacted for other relevant published and unpublished studies. SELECTION CRITERIA: All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-agonist. DATA COLLECTION AND ANALYSIS: Potentially relevant trials, identified by screening titles and/or abstracts, were obtained. Two reviewers independently assessed full text versions of these trials to decided whether the trial should be included in the review, and assessed its methodological quality. Where there was disagreement between reviewers, this was resolved by consensus, or reference to a third party. Data were extracted by two independent reviewers. Inter-rater reliability was assessed by simple agreement. Study authors were contacted to clarify randomisation methods, provide missing data, verify the data extracted and identify unpublished studies. Relevant pharmaceutical manufacturers were also contacted. MAIN RESULTS: Six trials met the inclusion criteria. Five used salmeterol and one, biltoterol. They were of varying quality. There was a trend for salmeterol to improve FEV1 more than theophylline in three studies and salmeterol use was associated with more symptom free nights. Bitolterol, used in only one study, was reported to be less effective than theophylline. Subjects taking salmeterol experienced fewer adverse events than those using theophylline (Relative Risk 0.38; 95%Confidence Intervals 0.25, 0.57). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.51; 95%Confidence Intervals 0.30, 0.88) and gastrointestinal adverse events (Relative Risk 0.32; 95%Confidence Intervals 0.17, 0.59). REVIEWER'S CONCLUSIONS: Salmeterol may be more effective than theophylline in reducing asthma symptoms including night waking and improving lung function. More adverse events occurred in subjects using theophylline when compared to salmeterol.

Adrenergic beta-Agonists↗
PubMed2000

Continuous positive airway pressure versus theophylline for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Theophylline stimulation of breathing and continuous positive airways pressure have been used to prevent apnea and its consequences. OBJECTIVES: The main objective was to determine in preterm infants with recurrent apnea, if treatment with CPAP compared with treatment with theophylline leads to a clinically important reduction in apnea or use of mechanical ventilation, without clinically important side effects. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. This includes searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE, previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching mainly in the English language. SELECTION CRITERIA: All trials using random or quasi-random allocation to CPAP or theophylline in preterm infants with clinical recurrent apnea/bradycardia were eligible. DATA COLLECTION AND ANALYSIS: Data were extracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk. MAIN RESULTS: The use of mask CPAP is associated with a higher treatment failure rate as measured by less than a 50% reduction in apnea or use of the alternative treatment [RR 2.89 (95% CI 1.12,7.47); RD 0.42 (95% CI 0. 11, 0.74)]. For every 2.4 infants (95% CI 1.4, 9.5) treated with mask CPAP rather than theophylline, there results one treatment failure. In the mask CPAP group there is more use of IPPV [RR 3.09 (1.42,6.70; RD 0.58 (95% CI 0.30, 0.86). For every 1.7 infants (95% CI 1.2, 3.3) treated with mask CPAP rather than theophylline, one infant is intubated for IPPV. In the mask CPAP group, there are trends towards more deaths in the first year, and in death or major disability in survivors at follow up, which do not reach significance. There are no differences in rates of necrotizing enterocolitis or major disability in survivors at follow up. REVIEWER'S CONCLUSIONS: Theophylline is more effective than mask CPAP for preterm infants with apnea. Since CPAP is no longer administered by mask, the results of this review have limited importance for current clinical practice. Further evaluation of the benefits and harms of CPAP vs theophylline for preterm infants with apnea requires further trials in which CPAP is administered by current methods.

Apnea↗
PubMed1987

Inhibition of theophylline clearance by coadministered ofloxacin without alteration of theophylline effects.

The influence of multiple doses of ofloxacin (ORF 18489) on the disposition of theophylline was studied in 15 male volunteers. Subjects were confined in the Clinical Research Unit for 13 days and given a xanthine-free diet. A single dose (3 mg/kg) of theophylline was given orally, and blood samples were collected at fixed time intervals for 36 h. The concentrations of theophylline were measured with TDX (Abbott Diagnostics, Irving, Tex.), and clearance was calculated. Theophylline clearance was used to individualize subsequent doses to achieve average steady-state theophylline concentrations in plasma of 10 mg/liter. Individualized theophylline doses were administered every 8 h until steady-state conditions were reached. Theophylline clearance was determined again at steady state and on days 7 and 8. On day 8, ofloxacin (400 mg every 12 h) was given concomitantly with theophylline. Theophylline clearance was measured again on day 12, after the last theophylline dose. Administration of ofloxacin for 1 day did not change theophylline clearance, but coadministration for 4 days significantly decreased theophylline clearance by 12.1% (P less than 0.05). The area under the concentration-time curve for theophylline increased 9.9% (P less than 0.05), and average steady-state concentrations in plasma increased 10.3% (P less than 0.05). Despite changes in clearance, adverse effects of theophylline did not increase during coadministration of ofloxacin. Although statistically significant, the interaction between ofloxacin and theophylline is unlikely to be of major clinical importance.

Adolescent↗
PubMed2001

Effect of levofloxacin on theophylline clearance during theophylline and clarithromycin combination therapy.

OBJECTIVE: To report a case of decreased theophylline clearance by the addition of levofloxacin in a patient receiving theophylline and clarithromycin. CASE SUMMARY: A 59-year-old Japanese man who was receiving theophylline for emphysema experienced stimulation, insomnia, and tachycardia due to theophylline toxicity after clarithromycin and levofloxacin were added to the regimen. The combination of these agents resulted in a decrease in theophylline clearance to approximately 60% of the initial value obtained while the patient was receiving theophylline alone. The adverse effects disappeared after the dosage was reduced and the theophylline serum concentration decreased; however, there was no change in theophylline clearance. After discontinuation of levofloxacin, the theophylline serum concentration decreased, and theophylline clearance returned to the initial level even though clarithromycin was continued. DISCUSSION: Levofloxacin is believed not to influence the clearance of theophylline, although some new fluoroquinolones have been reported to do so. This case indicates that levofloxacin and clarithromycin inhibited theophylline metabolic pathways catalyzed by both CYP1A2 and CYP3A4 and resulted in the decrease in theophylline clearance. The clearance of theophylline, therefore, is not influenced by clarithromycin alone. CONCLUSIONS: Careful monitoring is required when levofloxacin is prescribed for patients who are taking clarithromycin with theophylline.

Anti-Infective Agents↗
PubMed1986

Dissolution of theophylline monohydrate and anhydrous theophylline in buffer solutions.

The dissolution kinetics of theophylline monohydrate and anhydrous theophylline were investigated with a rotating-disk apparatus in buffer solutions at 298 K under sink conditions. The observed dissolution rate of theophylline monohydrate under various conditions agreed well with predictions based on the Extended Simultaneous Chemical Reaction and Dissolution concept. Below 337 K, anhydrous theophylline is converted to theophylline monohydrate in contact with water. The dissolution profile of anhydrous theophylline can be divided into three phases: a pre-transformation phase: anhydrous theophylline dissolves; the transformation phase, during which its dissolution rate drops to the level of the theophylline monohydrate dissolution rate; and steady state, at which the dissolution rate of anhydrous theophylline equals the dissolution rate of theophylline monohydrate. The presence of theophylline monohydrate crystals at the dissolving surface was confirmed by IR spectroscopy and microscopic observation. The length of the transformation phase, depending on the characteristics of the diffusion boundary layer, varied with the experimental conditions (e.g., pH and rotation speed). It was concluded that during the dissolution process the disk is covered with theophylline monohydrate crystals that precipitate from the supersaturated medium adjacent to the disk surface, and that crystallization of theophylline monohydrate is a precipitation process controlled by hydrodynamic and diffusion parameters.

Buffers↗
PubMed1986

Intravenous aminophylline in patients already taking oral theophylline: effect on calculated dose of knowledge of serum theophylline concentration on admission.

Measurement of serum theophylline concentration is usually recommended before intravenous aminophylline is given to patients taking oral theophylline. Fifty patients with worsening airflow obstruction, all of whom were taking oral theophyllines and who had no contraindication to the use of parenteral aminophylline, were randomly allocated into two groups before treatment was given. The dose of aminophylline was calculated without (group A) and with (group B) knowledge of admission serum theophylline concentration. In group A a regimen incorporating corrections to account for factors affecting theophylline clearance was used in an attempt to represent a "knowledgeable" approach; in group B a formula incorporating the known serum theophylline concentration at the time of admission was used. All loading doses were given over 30 minutes as "mini infusions." The two groups were well matched for age, blood gas tensions, and severity of airflow obstruction. The results for four patients (one from group A and three from group B) were excluded from analysis after completion of the study. In each group the mean admission serum theophylline concentration measured (group A: 8.4 (SD 6.0)mg/l; group B: 7.2 (5.7)mg/l) and the aminophylline doses used (group A: loading bolus 172 (45.5)mg, infusion 815 (198)mg; group B: loading bolus 233(189)mg, infusion 788(214)mg) were similar. Mean serum theophylline concentrations during 24 hours' aminophylline treatment, number of patients with a serum theophylline concentration greater than 20 mg/l, symptoms of toxicity, and outcome were also similar in the two groups. Although satisfactory use of parenteral aminophylline was achieved for most patients without knowledge of serum theophylline concentration at the time of admission to hospital (with the aid of a "knowledgeable" clinical approach and constant infusion pumps), prompt measurement of serum theophylline concentration at the time of admission identified patients with either suboptimal or potentially hazardous theophylline concentrations.

Administration, Oral↗
PubMed1992

Effect of xanthine-related compounds on a theophylline assay using theophylline oxidase.

OBJECTIVE: This study investigated a new, nonimmunologic, enzymatic-based theophylline assay for the possible interference of a clinically achievable serum theophylline concentration by four xanthine-related compounds: pentoxifylline, 1-methylxanthine, allopurinol, and oxypurinol. RATIONALE: The enzyme theophylline oxidase is used in this assay kit to convert theophylline to 1,3 dimethyluric acid in the presence of cytochrome C. Cytochrome C is reduced to ferrocyte C, which is then measured by ultraviolet spectrophotometry at one minute and again at five minutes. The rate of appearance of ferrocyte C over this time is then related to a one-point 20-micrograms/mL (111-mumol/L) theophylline standard provided with the kit and the concentration of theophylline is calculated. Xanthine-related compounds have the potential to interact with theophylline oxidase via: (1) structural similarity, and (2) inhibition of xanthine oxidase, which increases theophylline metabolite concentrations. DESIGN: Human serum was spiked with known, therapeutically achievable concentrations of pentoxifylline, 1-methylxanthine, allopurinol, and oxypurinol, both alone and in combination with theophylline in a concentration of 15 micrograms/mL (83.3 mumol/L). Two controls were used: human serum and human serum spiked with theophylline. Data were analyzed statistically with ANOVA, and clinically with +/- 10 percent control criteria. RESULTS: Means (+/- SEM) for the control samples were 2.0 (0.2) micrograms/mL for serum alone and 15.3 (0.3) micrograms/mL for theophylline-spiked serum. For the test specimens, the results ranged from 2.3 to 2.8 micrograms/mL and from 13.9 to 16.6 micrograms/mL when xanthine-related compounds were added to serum without and with theophylline, respectively. CONCLUSIONS: The results were not statistically or clinically significant for the four xanthine-related compounds at the concentrations studied.

Allopurinol↗
PubMed1992

Impact of therapeutic drug monitoring of intravenous theophylline regimens on serum theophylline concentrations in the medical intensive care unit.

OBJECTIVE: The primary objective of this study was to determine if a clinical pharmacist ensuring appropriate use and performing careful pharmacokinetic analysis of serum theophylline concentrations (STCs) can result in optimal theophylline regimens for patients in a medical intensive care unit (ICU). DESIGN: In phase 1 of the study, housestaff physicians determined the theophylline dosing regimen. A clinical pharmacist prospectively followed these initial patients, but did not intervene. Patients in phase 2 received intravenous theophylline, with all dosing regimens being based on prospective therapeutic drug monitoring (TDM) by a clinical pharmacist. PARTICIPANTS: The first phase enrolled 11 consecutive patients admitted into the medical ICU and requiring intravenous theophylline. This was followed by a second phase of 14 medical ICU patients whose intravenous theophylline regimen was determined by a clinical pharmacist performing pharmacokinetic analysis. MAIN OUTCOME MEASURES: Questions were organized into the following sections: (1) number of STC blood samples drawn, (2) number of emergency STCs performed, (3) number of concentrations per infusion-rate changes, (4) number of STC results in the pharmacist-generated regimens that were within the physicians' predetermined acceptable range. RESULTS: In phase 1, 27 theophylline rate changes occurred, with a mean +/- SD of 1.01 +/- 0.3 STCs per day. In phase 2, 44 theophylline infusion rates were changed, with a mean +/- SD of 0.62 +/- 0.3 STCs per day. The TDM group had a significant reduction (p less than 0.001) in inappropriate concentrations (15 vs. 40 percent) as set by predetermined criteria, and fewer emergency theophylline concentration requests (2 vs. 14). Serum theophylline concentrations ordered by the physician were achieved in 85 percent of the pharmacist-generated regimens. CONCLUSIONS: Pharmacokinetic analysis when performing TDM in the determination of intravenous theophylline regimens can result in optimal therapy for patients, while significantly reducing the number of STCs required.

Adult↗
PubMed1986

Theophylline plus hydroxyzine versus theophylline monohydrate in the treatment of asthma.

The efficacy of 281.7 mg of theophylline monohydrate and a combination of theophylline (240 mg) + hydroxyzine (7.5 mg) were compared in a double-blind, crossover, placebo-controlled study in 15 patients with chronic reversible bronchial asthma. The patients took the drugs tested at 7.00 a.m., 3.00 p.m. and 10.00 p.m. During the 3-day trial period, the patients measured their peak expiratory flow (PEF) values every day at 7.00 a.m., 10.00 a.m. and 10.00 p.m., and during the last trial day, theophylline serum levels were also determined. Use of theophylline monohydrate resulted in slightly steadier serum theophylline levels than with theophylline + hydroxyzine and morning levels of theophylline were significantly higher (p less than 0.01) during the former treatment. Despite this, only the theophylline + hydroxyzine combination had a significant effect (p less than 0.05 at 7.00 a.m., p less than 0.01 at 10.00 a.m. and 10.00 p.m.) on PEF values at each time of measurement. There was a significant difference (p less than 0.05) in PEF values at 10.00 a.m. between the trial preparations in favour of the theophylline + hydroxyzine combination. Theophylline + hydroxyzine significantly decreased (p less than 0.05) nocturnal dyspnoea and most patients preferred this preparation. The differences in side effects were not statistically significant. The addition of hydroxyzine to theophylline increases the clinical efficacy of the latter.

Adult↗
PubMed1983

Pharmacokinetics of theophylline and bioavailability of a sustained release theophylline preparation in patients with cystic fibrosis.

The elimination of theophylline after intravenous aminophylline bolus and the absorption of a sustained-release oral theophylline preparation (Theo-Dur) were studied in ten patients with cystic fibrosis (C.F.). Each patient received an I.V. bolus of aminophylline equivalent to 4 mg/kg anhydrous theophylline and 10 plasma theophylline levels were obtained over the following eight hours. Elimination half life (T1/2), total body clearance (Cl), volume of distribution (Vd) and area under the concentration curve (AUCiv) were determined. Forty-eight hours later each patient received an oral dose of sustained release theophylline equivalent to 7.47-11.42 mg/kg anhydrous theophylline and 13 plasma theophylline concentrations were measured over 24 hours. Area under the concentration curve (AUCpo) and fractional absorption (F) of the sustained release preparation were determined. Mean values (+/- S.D.) were T1/2 = 4.45 +/- 1.58 hrs, Vd = 505.8 +/- 40.7 ml/kg, Cl = 87.9 +/- 31.6 ml/kg/hr, F = 0.86 +/- 0.26. One patient did not develop detectable plasma theophylline levels until 20 hours after receiving the sustained release product, but rapidly absorbed 96% of orally administered theophylline elixir. While we could demonstrate no consistent abnormality of theophylline distribution or elimination in cystic fibrosis patients, large interindividual differences in elimination may exist. In addition, some C.F. patients may have impaired or delayed absorption of sustained release theophylline preparations.

Adolescent↗
PubMed1991

Nonlinear theophylline pharmacokinetics. A preventable cause of iatrogenic theophylline toxic reactions.

When theophylline is used for the treatment of patients with obstructive pulmonary diseases, most clinicians attempt to maintain serum levels between 55 and 110 mumol/L because higher levels are associated with an increased risk of serious toxic effects. Nonlinear theophylline kinetics are known to occur in animals, in some pediatric patients, and at very high toxic levels in adults. However, within the usual therapeutic range of serum levels, first-order kinetics are assumed to operate, and, thus, a one-compartment model or a model-independent approach is routinely used for dose adjustments. We have recently encountered two adult patients in whom nonlinear theophylline kinetics existed within the subtherapeutic and therapeutic range of serum levels. In both cases this was not immediately recognized by the clinician, resulting in prolonged use of subtherapeutic doses of theophylline. In addition, in one case our empiric attempts to achieve therapeutic serum levels resulted in serious theophylline toxicity. We present only the data from this latter patient to be used as a case study. Based on this example and a review of the literature, we propose that to avoid such a potentially fatal complication the following steps should be taken when dealing with a patient in whom serum theophylline levels fail to rise as expected with increasing oral doses: (1) supervised administration of oral theophylline to rule out noncompliance; (2) discontinuation of further empirical increases of the oral dose of theophylline; (3) obtention of steady-state serum levels on at least two different oral doses of theophylline; and (4) calculation of the appropriate maintenance dose of theophylline for that individual patient using any of the methods cited in this report.

Drug Administration Schedule↗
PubMed1982

Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects.

Therapeutic response to theophylline in asthma is generally attributed to its effect in increasing intracellular 3',5' cyclic adenosine monophosphate (cAMP) by competitive inhibition of cAMP phosphodiesterase. However, because of discrepancies between therapeutic serum theophylline concentration achieved clinically and those required for in vitro phosphodiesterase inhibition, we explored the possibility that theophylline may act through adrenomedullary secretion of catecholamines. Five healthy, nonasthmatic male and female adults were studied with a double-blind, randomized, crossover protocol. Theophylline (5 mg/kg) and placebo were administered in a capsule dosage form. Plasma catecholamines epinephrine (E), norepinephrine (NE), and dopamine (DA) were measured by a radioenzymatic assay at baseline and after administration of theophylline at 1, 2, and 3 hr. Significant differences between theophylline- and placebo-treated groups (p less than 0.05) were seen at 3 hr for mean percentage increase over baseline with E (120% +/- 25.3%) and NE (48.02% +/- 17.94%) after theophylline therapy (mean peak level 7.2 +/- 0.48 micrograms/ml). Epinephrine plasma concentration was significantly greater (p less than 0.001) at 3 hr compared with baseline (105 +/- 16 vs 56 +/- 18 pg/ml), while NE (448 +/- 52 vs 320 +/- 36 pg/ml) did not attain significance (p = 0.136). A significant correlation (p less than 0.05) was found between the percentage increase over basal for E (r = 0.58) and NE (r = 0.66) and serum theophylline levels. DA was not significantly increased at any time period. Thus theophylline in clinically relevant concentration appears to stimulate adrenomedullary secretion of catecholamine. Whether this is an important mechanism of action in asthma or explains some side effects of theophylline remains to be determined.

Adrenal Medulla↗