The use of parenteral aminophylline in patients taking slow release theophylline preparations: an observation of clinical practice

Parenteral theophylline usage was studied in 53 patients with worsening airflow obstruction who had been prescribed slow release theophylline drugs and were admitted to a hospital lacking facilities for rapid serum theophylline concentration estimation. Individual clinicians varied in their practice with respect to parenteral aminophylline, but in general its use was favoured in patients with asthma rather than simple chronic airflow obstruction. There was no significant difference in admission serum theophylline concentrations between 31 patients who were subsequently given intravenous aminophylline and 22 who were not. There was also no significant difference in admission serum theophylline concentrations between ten patients given an aminophylline bolus and an infusion, seven patients given a bolus alone and 14 patients given an infusion alone. Individual patient's serum theophylline concentrations were variable during infusions and often suboptimal. The results indicate that the use of parenteral aminophylline in patients receiving slow release theophyllines is imprecise and possibly hazardous without facilities for prompt serum theophylline concentration estimations. This facility should be available in hospitals where parenteral aminophylline is used.     

The influence of orally administered cimetidine and theophylline on the elimination of each drug in patients with chronic airways obstruction

We studied the effect of cimetidine and theophylline on the metabolism of each drug in 19 elderly patients with stable chronic obstructive pulmonary disease. Each patient received either regular release or sustained release oxtriphylline. Cimetidine was given to some patients in both groups after steady state for theophylline was achieved. Multiple serum theophylline and cimetidine measurements were performed. Cimetidine decreased theophylline clearance by an average of 37.8% (26.2 to 46.7) for regular release and 33.4% (22.2 to 45.0) for sustained release oxtriphylline. The apparent volume of distribution was not changed; however, the half-life for theophylline was increased. As there is a linear relationship between the theophylline clearance before and after the addition of cimetidine and a linear relationship between trough and peak values before and after cimetidine, these 2 relationships may be used to predict clearance values and serum levels after cimetidine treatment when the initial values are known.     

A double-blind, placebo-controlled comparison of the efficacy of standard and individually titrated doses of theophylline in patients with chronic asthma

Forty adult patients with chronic asthma completed a 3-month double-blind crossover study to compare the effect of sustained-release theophylline given both as a fixed 300 mg twice daily dose (standard) and an individually titrated dose (titrated) with placebo. Theophylline was given in addition to other usual therapy, inhaled bronchodilators, inhaled steroids and, in 12 patients, oral steroids. The 3-month period was preceded by a run-in phase to determine the dose of theophylline which each subject required to achieve peak serum levels of 12-20 mg/litre and trough levels of 8-12 mg/litre. Doses ranged from 300 mg to 700 mg twice daily. Twenty-one patients needed more than the standard dose to achieve satisfactory serum levels. Patients recorded daily peak flow rates and symptom scores and were seen at monthly intervals to measure lung function, check serum theophylline levels and change treatments, which were given in random order. FEV1 was significantly higher for the whole group after standard (2.11 litres) and titrated (2.15 litres) theophylline therapy than after placebo (1.89 litres), as was FVC, but in the large subgroup whose titrated dose was greater than the standard dose, the FEV1 only improved with the titrated dose. Peak flow measurements at home showed the same pattern. Patients taking oral steroids appeared to derive less benefit from theophylline than others. It is concluded that theophylline can usefully be added as a third-line drug in chronic asthma, but that since half the patients are likely only to benefit from a dose greater than 300 mg twice daily, while the other half may have high serum levels above this dose, it is essential to measure serum levels in order to use the drug effectively and safely.     

Steady-State Evaluation of Twice-a-Day Dosing of a New Sustained-Release Theophylline Preparation for Young Children

We studied the absorption properties of a new sustained-release theophylline, Theo-Dur Sprinkle® (TS), to see if this formulation when given on a b.i.d. basis results in acceptable steady-state theophylline levels in children with asthma. Twelve patients (ages 5–8 years), after multiple TS dosing, had serum theophylline levels determined over a 10-hr period after a morning TS dose. Fluctuations in serum theophylline concentrations were acceptable with the observed mean percent peak-to-trough fluctuation [(peak -trough/trough) x 100] being 53%. Patients required higher than usually recommended theophylline doses to obtain therapeutic levels, suggesting incomplete absorption of TS; this was documented with one patient using a 100% bioavailable theophylline product as a comparison.     

Steady-state evaluation of twice-a-day dosing of a new sustained-release theophylline preparation for young children

We studied the absorption properties of a new sustained-release theophylline, Theo-Dur Sprinkle® (TS), to see if this formulation when given on a b.i.d. basis results in acceptable steady-state theophylline levels in children with asthma. Twelve patients (ages 5-8 years), after multiple TS dosing, had serum theophylline levels determined over a 10-hr period after a morning TS dose. Fluctuations in serum theophylline concentrations were acceptable with the observed mean percent peak-to-trough fluctuation [(peak -trough/trough) x 100] being 53%. Patients required higher than usually recommended theophylline doses to obtain therapeutic levels, suggesting incomplete absorption of TS; this was documented with one patient using a 100% bioavailable theophylline product as a comparison.     

Effect of Theophylline on Serum Uric Acid Levels in Children with Asthma

This study was undertaken to investigate the effect of theophylline on serum uric acid levels in children with asthma. Twenty-seven asthmatic children, including 21 patients who were treated with slow-release theophylline and 6 patients not receiving any type of theophylline preparation, were enrolled in this study. Serum uric acid levels were increased in the asthmatic children treated with theophylline compared to those not receiving this agent (6.28 ± 0.29 mg/dl, mean ± SEM, vs. 4.82 ± 0.52 mg/dl, p < 0.05). A significant positive correlation between the serum levels of uric acid and theophylline was demonstrated in the patients of this study (r_s = 0.5%, p < 0.01). All the patients in whom theophylline administration was stopped showed significant decreases in serum uric acid levels (p < 0.05). From these results, we conclude that theophylline increases serum uric acid levels in children with asthma, just as it does in adult asthmatics.     

Theophylline serum levels in children with bronchial asthma after administration of slow release theophylline as open or closed capsules

Theophylline serum levels were studied after oral administration of slow release theophylline (Talofilina) in children with bronchial asthma. The children received the drug as closed capsules or as granules, obtained by opening the capsules, for 1 week in each form. The mean dose used was 8.6 mg/kg every 12 h. The theophylline blood levels at 4, 8 and 12 h after drug ingestion were significantly lower when granules from open capsules were used. Our recommended dose of Talofilina for Brazilian children is 16 mg/kg/day, if administered as closed capsules, every 12 h. On open capsule administration every 12 h, the total daily recommended dose is 20 mg/kg/day.     

Electrophysiologic effects of theophylline in young patients with recurrent symptomatic bradyarrhythmias

In this study, both acute electrophysiologic actions of intravenously administered theophylline and clinical effects of chronic oral theophylline therapy were assessed in 10 young patients (aged 9 to 41 years) without clinically significant cardiac disease, in whom recurrent symptoms of syncope and dizziness were attributed to transient bradyarrhythmias (sinus pauses, marked sinus bradycardia or paroxysmal atrioventricular [AV] block). Intravenous theophylline infusion (serum concentration range 9.5 to 12.0 mg/liter) shortened means sinus cycle length (control 973 ± 285 ms versus theophylline 880 ± 226 ms, p <0.005) and decreased both the estimated sinoatrial conduction time (control 169 ± 56.0 ms versus theophylline 143 ± 55.3 ms, p <0.05) and the maximum corrected sinus node recovery time (control 442 ±251.0 ms versus theophylline 255 ± 146.2 ms, p <0.05). In addition, theophylline infusion shortened the minimum atrial paced cycle length with sustained 1:1 AV conduction (control 414 ± 86 ms versus theophylline 379 ± 97 ms, p <0.05) and consistently reduced AV node functional refractory periods. Subsequent chronic oral theophylline therapy (serum levels 9 to 12 mg/liter) was tolerated in 8 patients (80%). During a follow-up of 5 to 24 months, suppression of symptoms was achieved in 6 of the 8 patients. Thus, theophylline exhibits positive chronotropic and dromotropic effects in man at serum concentrations in the usual therapeutic range (10 to 15 mg/liter). Furthermore, suppression of symptoms during follow-up suggests that theophylline treatment may be a useful therapeutic consideration in some patients with recurrent symptomatic bradyarrhythmias.     

Comparison of a new sustained-release theophylline preparation, TheoBeads, with Theo-Dur tablets in children with asthma

A new, slow-release theophylline formulation for children, TheoBeads, which has the potential for once-daily dosing, has become available. We report the results of a study of pediatric patients whose medication was changed from Theo-Dur tablets b.i.d. to TheoBeads q.d. Forty-nine children with asthma (aged 6-12 years) were treated with b.i.d. Theo-Dur to produce therapeutic maximum and minimum concentration levels (i.e., 8-20 micrograms/ml). Approximately half the patients were then transferred to TheoBeads given q.d. at the same total daily dose and retitrated; seven patients needed to be changed to b.i.d. dosing due to unacceptable fluctuations. The other half of the patients continued on b.i.d. Theo-Dur. Following at least 5 days of steady-state dosing, serum theophylline levels were assayed over a 24-hour period. It was found that: 1. Children changed to q.d. TheoBeads showed no change in their overall asthma control based on clinical diary entries and peak flow measurements. 2. Lower Cmax and Cmin theophylline levels and a smaller area under the curve were noted for patients taking q.d. TheoBeads compared to those taking b.i.d. Theo-Dur. 3. Administration of TheoBeads q.d. resulted in a significantly larger overall peak-to-trough fluctuation and a higher percentage of patients with subtherapeutic theophylline levels in the second 12-hour period than did b.i.d. Theo-Dur administration. In summary, when children receiving b.i.d. Theo-Dur were transferred to q.d. TheoBeads, they did not maintain even and sustained therapeutic theophylline levels, although asthma control was not adversely affected during the short period of observation.     

Effect of theophylline on endogenous hydrogen sulfide production in patients with COPD

BACKGROUND: Airway inflammation plays a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Endogenous hydrogen sulfide (H2S) is involved in the physiological and pathophysiological process in systemic inflammation and may be involved in the pathogenesis of airway inflammation and airflow obstruction in COPD. The non-selective phosphodiesterase inhibitor theophylline has bronchodilator/anti-inflammatory properties and is widely used in the treatment of airways diseases. It is not fully understood whether endogenous H2S mediates the mechanism of theophylline anti-inflammatory effect. METHODS: The effect of short-term theophylline treatment on airway inflammation and endogenous H2S production was prospectively studied in thirty-seven patients with stable COPD. Patients were randomly divided into theophylline-treatment group (nineteen patients, orally given sustained theophylline tablets for 1 month, 0.2g, q 12h) and control group (eighteen patients, not given any theophylline). Symptom score, lung function, total and differential cell counts in sputum, serum H2S and nitric oxide (NOx) levels, sputum and serum IL-8 levels were measured at baseline and 1 month later. RESULTS: No significant difference was found in symptom scores, lung function and other investigated experimental parameters at baseline between treatment and control groups, and between baseline and a month follow-up in control patients. Symptom scores were significantly lowered only in the treated patients after treatment, compared with those before (P<0.01). The proportion of neutrophils in sputum was significantly decreased (P<0.05) while that of macrophages was markedly increased (P<0.01) in the treated patients after treatment, compared with that before. No significant change was found in serum H2S and NOx levels, serum and sputum IL-8 levels before and after experiment in treatment group. Serum H2S level correlated positively with percentage of predicted FEV1 (r=0.465, P=0.005), and with proportion of sputum macrophages (r=0.349, P=0.05), but negatively with proportion of sputum neutrophils (r=-0.351, P=0.049) in all patients at baseline. CONCLUSIONS: Short-term theophylline treatment improved symptoms and decreased sputum neutrophils in COPD, while serum H2S levels were not affected in our study population. Large samples will be needed to illustrate the effect of long-term theophylline treatment on inflammatory mediators and H2S generation in COPD.     

Pharmacokinetics of sustained release and conventional tablets of theophylline plus hydroxyethyltheophylline and its comparison with tablet aminophylline.

Pharmacokinetics of a sustained release (SR) and conventional formulations of theophylline plus hydroxyethyltheophylline was compared with tablet aminophylline. Time concentration curve of serum theophylline with the three formulations after single and multiple dosage schedules revealed significantly retarded absorption with the SR preparation. SR tablet was also seen to produce uniform steady state levels with fluctuation of serum concentrations within the therapeutic range for a duration of over 12 hours. In comparison, aminophylline and conventional theophylline hydroxyethyltheophylline tablets produced sharp swings in steady state levels with trough levels dipping to subtherapeutic concentrations within 4-6 hours. SR formulation, therefore, is likely provide consistent serum levels and better therapeutic control in comparison to the other two conventional tablets.     

Nocturnal asthma: slow-release terbutaline versus slow-release theophylline therapy

In a double-blind cross-over study, the effects of slow release (S-R) terbutaline tablets (b.i.d. 0.25 mg/kg per day) and S-R theophylline (5.31 mg/kg morning and 10.62 mg/kg evening) were compared in eleven patients with nocturnal asthma. On day seven of each treatment period, drug serum concentrations and peak expiratory flow (PEF) were measured every 2h over a 24-h period. During daytime, terbutaline concentrations ranged from 1.6-14.1 (median 4.5) microgram/l and during the night from 2.1-18.7 (median 4.9) micron/l. Theophylline concentrations ranged from 3.9-24.3 (median 11.5) mg/l during the day and from 3.3-20.9 (median 10.4) mg/l at night. Nocturnal wheezing occurred during theophylline treatment in four patients 7 times and during terbutaline treatment in six patients 22 times. Daytime PEF values were 472 +/- 161 l/min during theophylline therapy versus 445 +/- 169 l/min during terbutaline therapy (p less than 0.05). In the night and early morning there was no significant difference between PEF values with the two treatment forms. During theophylline treatment, fewer inhalations of beta 2-sympathomimetics were used, and there were fewer side effects. One patient experienced severe asthmatic attacks during the terbutaline treatment period. The patients preferred theophylline for the treatment of nocturnal asthma.     

Evaluation of a sustained-release theophylline product in children with asthma

The purpose of this study was to determine the dose requirements and dose interval of a sustained-release theophylline sprinkle preparation (Somophyllin-12) necessary to maintain therapeutic serum theophylline concentrations in children with asthma. Eighteen patients aged 3-7 years (subgroup 1) and 21 patients aged 8-12 years (subgroup 2), who had been on continuous theophylline therapy with Somophyllin-12, completed the study. Prior to entry into the study, each patient's dosage of Somophyllin-12 was titrated to achieve predose and peak (4-hour postdose) theophylline levels in the therapeutic range (8-20 mg/L). The patients subsequently had predose and peak serum theophylline levels determined at baseline (week 0) and at weeks 2 and 4 of the study. The majority of children maintained theophylline levels in the therapeutic range throughout the 4-week trial, and t-tests showed no significant change from baseline in mean values of peak, trough, or peak-trough theophylline differences in either patient subgroup at weeks 2 and 4. Nevertheless, some individual patients had considerable variation from baseline in peak and trough theophylline levels at follow-up visits. Dosage requirements standardized for weight were significantly higher in patients in subgroup 1 than in subgroup 2 (21.3 +/- 4.5 mg/kg per day versus 17.5 +/- 4.7 mg/kg per day; p less than 0.05). The majority of the patients required 12-hourly administration of Somophyllin-12, but seven of 39 patients required 8-hour dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Life-threatening theophylline toxicity is not predictable by serum levels

We questioned whether there was any way to predict which patients with high serum theophylline levels would develop life-threatening toxicity and thereby determine which patients might benefit from prophylactic therapeutic measures, such as hemoperfusion or hemodialysis. We reviewed the records of 54 consecutive patients seen over a five-year period in whom the serum theophylline level was 39 micrograms/ml or higher (range 39-78 micrograms/ml, mean theophylline level 49.5 +/- 9.6 micrograms/ml). Toxicity sought included cardiovascular--major arrhythmias (asystole, ventricular tachycardia, ventricular fibrillation) and minor arrhythmias, (central nervous system--major [seizures], minor [confusion, agitation]); and gastrointestinal (nausea, vomiting and diarrhea). In our sample of patients with extremely high theophylline levels, the incidence of life-threatening complications was low, and the subgroup of patients with high serum theophylline levels who developed life-threatening toxicity could not be easily identified. We conclude that major interventional procedures such as hemoperfusion or hemodialysis should not be used prophylactically in this population of patients of middle age to elderly men with high theophylline levels. We recommend a more conservative approach of using oral activated charcoal therapy in all patients with high serum theophylline levels, and reserving hemoperfusion or hemodialysis for those patients who develop seizures or major arrhythmias.     

Intravenous aminophylline in the treatment of acute bronchospastic exacerbations of chronic obstructive pulmonary disease

Often chronic obstructive pulmonary disease (COPD) patients treated for acute exacerbations receive intravenous (IV) aminophylline in addition to inhaled bronchodilators that may raise serum levels of theophylline into the toxic range. A double-blind, randomized study of 52 men with COPD who came to the emergency department for treatment of exacerbations was initiated to establish the efficacy and safety of this common practice. After history and physical examination, patients were treated with 28% oxygen by Venturi mask and 0.3 cc metaproterenol sulfate in 2.5 cc saline by nebulizer; an IV line was started and patients received either aminophylline or D5W. Measurements included baseline and two-hour serum theophylline levels, pulmonary function tests, and symptom questionnaires. Mean values from the entire group showed decreases in respiratory rate, cardiac rate, and pulsus paradoxus, and increases in forced expiratory volume in one second (FEV1) and vital capacity (VC) over a two-hour treatment period (P less than .01). Despite the increase in serum theophylline in the treatment group, the demographic, clinical, pulmonary function, and outcome data were found to have no statistically significant differences when compared to control patients. The data were then analyzed according to serum theophylline levels. Theophylline level greater than 20 micrograms/mL occurred in 15 patients with no untoward effects; premature ventricular contractions (PVCs) were no more frequent in this group than in those with lower serum theophylline levels. A theophylline level greater than 10 micrograms/mL after two hours of treatment resulted in the following differences, which were not statistically significant: mean FEV1 response less than or equal to 10 micrograms/mL vs greater than 10 micrograms/mL, 20% vs 28%; mean VC change, 17% vs 30%; or mean emergency department returns in one week, 0.1 vs 0.26. In our experience, oxygen and inhaled metaproterenol are effective treatment for exacerbations of COPD.     

Utilisation de la théophylline dans les états bronchospastiques graves

The aim of this study was to assess the variations in plasma theophylline in 40 patients with chronic obstructive airways disease (COAD) presenting with acute respiratory failure and treated with continuous intravenous theophylline infusion. High performance liquid chromatography was used to measure the theophyllic levels.The results show a wide variation in theophyllic clearance (mean 41,34 ml/kg/hr). No correlations were found between plasma levels and smoking, obesity, pH, pa CO2, pa 02, HC03, serum albumin, serum bilirubin or hepatic enzyme levels. This variability was observed not only between different patients but also in the same patient at different stages of acute respiratory failure. The theophylline clearance levels were significantly lower than in a control population — 80 to 100 ml/kg/hr) and suggest that theophylline dosage should be reduced in patients with chest disease in severe, acute respiratory failure.     

Long-term treatment with theophylline reduces neutrophils, interleukin-8 and tumor necrosis factor-alpha in the sputum of patients with chronic obstructive pulmonary disease

BACKGROUND: The non-selective phosphodiesterase inhibitor theophylline has bronchodilator/anti-inflammatory properties and is widely used in the treatment of airways diseases. We determined the effect of long-term theophylline treatment on airway inflammation in patients with chronic obstructive pulmonary disease (COPD). POPULATIONS AND METHODS: Seventeen stable COPD patients were enrolled in the 12-month study. Theophylline was administered at 400mg/day. We studied changes in symptoms, spirometry, sputum volume, and sputum inflammatory cytokines levels. We also examined the effects of theophylline on the release of inflammatory cytokines in vitro by measuring interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha levels from lipopolysaccharide (LPS)-stimulated neutrophils and THP-1 cells. RESULTS: Forced vital capacity was increased and sputum IL-8 levels decreased after 4 weeks of theophylline treatment. After 6 months of theophylline treatment, forced expiratory volume in 1s was increased, and neutrophils counts and TNF-alpha levels in sputum were reduced. Levels of IL-8 and TNF-alpha released by LPS-stimulated THP-1 cells were reduced by treatment with theophylline at 10microg/ml. In contrast, IL-8 levels released by LPS-stimulated neutrophils were reduced by treatment with theophylline at 100microg/ml. CONCLUSION: Our clinical study of small population showed that long-term treatment with theophylline seems to reduce airway inflammation in stable COPD patients.     

Relative resistance to oral theophylline treatment in patients with hyposmia manifested by decreased secretion of nasal mucus cyclic nucleotides

IntroductionOral treatment with the phosphodiesterase inhibitor theophylline in an open-label fixed-design clinical trial in 312 patients with hyposmia improved smell function in > 50%. Before treatment, all patients had lower than normal levels of nasal mucus cAMP and cGMP. The purpose of this study was to study relationships among changes in smell function, theophylline levels and nasal mucus cAMP and cGMP among patients whose smell function improved (responders) and those who did not improve (nonresponders) on oral theophylline treatment.MethodsAfter all data analysis from the clinical trial was completed, data from each of the 31 of the 312 patients in whom nasal mucus cAMP and cGMP and theophylline levels were available before and after theophylline treatment at several drug doses were evaluated. At initiation and at termination of each treatment, dose smell function, nasal mucus cAMP and cGMP and plasma theophylline were analyzed.ResultsOn the same theophylline dose, although serum theophylline increased among both responders and nonresponders, serum levels were consistently higher among responders. Nasal mucus cAMP and cGMP were also higher among responders than nonresponders. At higher theophylline doses, cGMP reached normal levels among responders, whereas it did not change significantly among nonresponders.ConclusionsSome patients with hyposmia with initially low nasal mucus cAMP and cGMP levels may be relatively resistant to oral theophylline treatment. This result may offer a mechanism of response lack among some patients whose smell function did not improve after oral theophylline treatment although other factors may influence their response lack.     

A prospective evaluation of elevated serum theophylline concentrations to determine if high concentrations are predictable

PURPOSE: To evaluate prospectively whether serum theophylline concentrations of 25 mg/L and greater were predictable (and presumably preventable) by use of basic pharmacokinetic calculations. DESIGN: Prospective study. PATIENTS: Fifty-five patients with a serum theophylline concentration of at least 25.0 mg/L were evaluated initially and if subsequent elevated theophylline concentrations occurred. INTERVENTIONS: The predicted steady-state serum theophylline concentration was calculated from the dosage rate divided by the predicted clearance to determine how many elevated concentrations (greater than 20 mg/L) were predictable. Predicted clearances were 0.04 L/kg/hour for normal subjects less than 70 years of age and 0.02 L/kg/hour for patients with congestive heart failure, chronic obstructive pulmonary disease, or liver disease. Estimated clearances were determined and compared with predicted clearances. If patients did not have steady-state concentrations, additional calculations were made. MAIN RESULTS: From 6,368 consecutive theophylline determinations, 69 (1.08%) samples from 55 patients were 25 mg/L or higher. Predictably high concentrations occurred in 23 of 33 (69.7%) fully evaluable cases. These concentrations occurred because of a failure to consider decreased elimination clearance from congestive heart failure, chronic obstructive pulmonary disease, or hepatic disease. Five fatalities occurred, and in two cases, theophylline appeared to contribute to the patient's death. Three other patients experienced syncope. The predicted elimination clearance of theophylline of 0.02 L/kg/hour was too high in eight patients over 70 years old with cardiac or pulmonary disease. Nursing and pharmacy oversights were identified as three patients were given two theophylline products simultaneously. CONCLUSIONS: Most elevated theophylline concentrations are predictable (and preventable) by basic pharmacokinetic calculations. Patients experiencing elevated theophylline concentrations often had comorbid conditions and were greater than 60 years of age. The dosage rate of theophylline (mg/hour) can be estimated from predicted clearance (L/kg/hour) times desired steady-state serum concentration (mg/L).     

The effect of mexiletine on theophylline pharmacokinetics in patients with bronchial asthma]

Reported side effects of mexiletine, a useful drug for managing premature ventricular contractions (PVC) and ventricular tachycardia (VT), are gastrointestinal symptoms including nausea and vomiting. Theophylline, a bronchodilator, also causes similar gastrointestinal symptoms with its frequency proportional to the increases in its serum concentration. The occurrence of gastrointestinal symptoms is known to increase in combination therapy of mexiletine and theophylline. However, the pharmacokinetic interaction between mexiletine and theophylline has not been clarified. We, therefore, investigated the effects of mexiletine on theophylline pharmacokinetics. Three patients with bronchial asthma complicating PVC and/or VT (one male and 2 females, aged 70.0 +/- 13.1 years) were studied. All patients were given prophylactic theophylline anticipatory for asthmatic attacks, which was followed by oral administration of mexiletine, 200-300 mg daily, for PVC and/or VT. The serum theophylline concentrations in 3 cases were increased from 13.8 to 25.3 micrograms/ml, from 14.6 to 27.8 micrograms/ml, and from 10.4 to 15.4 micrograms/ml, respectively, after the administration of mexiletine. However, significant decreases in theophylline clearance were observed after the administration of mexiletine by 46, 47 and 35%, respectively. (p < 0.05) With a decrease in theophylline dosage, the serum theophylline concentrations decreased, and gastrointestinal symptoms resolved. Theophylline is metabolized mainly in the liver through an oxidative reaction of p-450 enzyme, however, its metabolism is affected by many factors, such as medications and complications. The results of this study indicated that mexiletine decreases the theophylline clearance by inhibiting the p-450 oxidative reaction to theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)