Sustained-release Theophylline Research Articles

Population-based open-label clinical effectiveness assessment of the cysteinyl leukotriene receptor antagonist pranlukast

Although the efficacy of cysteinyl leukotriene receptor antagonists in asthma therapy has been established through controlled clinical trials, there are no data concerning the effectiveness of their use in clinical practice, in which there is no rigid selection based on specific inclusion and exclusion criteria. The aim of the present study was to evaluate the effectiveness of pranlukast in clinical practice. More than 2500 outpatients with mild to severe persistent asthma answered an input questionnaire, which consisted of 33 items assessing asthma symptoms in terms of six activities of daily living during the previous 2 weeks. Of these patients, 1138 received treatment with pranlukast and answered the same questionnaire 4–6 weeks after the start of treatment. In 923 of these 1138 patients, we examined the impact of concomitantly used inhaled steroids, β2-adrenergic agonists or sustained-release theophylline on the effectiveness of pranlukast treatment. One hundred and sixty-seven control patients completed the questionnaire twice but did not receive pranlukast treatment. We found a significant decrease in the number of asthma symptoms reported among both the 1138 patients treated with pranlukast and the 167 control patients. However, the magnitude of the decrease in symptoms was significantly (P < 0.001) greater with pranlukast treatment. Moreover, pranlukast was equally efficacious in the presence and absence of concomitantly used inhaled steroids, β2-adrenergic agonists or sustained-release theophylline. In conclusion, pranlukast was shown to have clinical effectiveness in the treatment of mild to severe persistent asthma symptoms.

Use of prophylactic medication in persistent asthma

OBJECTIVE: To assess the proportion of patients with moderate or severe persistent asthma who are on prophylactic therapy when first evaluated at a specialized outpatient center. METHODS: Descriptive study of 306 patients with persistent asthma and ages ranging from four to fifteen years old, seen from June/1995 to August/1998, at the Respiratory and Allergic Diseases section of the Child and Adolescent Institute, an outpatient reference center located in the town of Juiz de Fora (MG), Brazil. Data from the Institute's registry, chiefly those related to the use of prophylactic medications, such as inhaled steroids, sodium chromoglycate, nedocromil sodium, sustained-release theophylline, long acting inhaled beta2-agonist and ketotifen were used to fill in a standardized protocol. RESULTS: Of the 306 patients, 87.3% had persistent moderate and 12.7% had persistent severe asthma. Only 14.4% were on some kind of controller medication. When only the use of inhaled antiinflammatory drugs (sodium cromolyn, nedocromil sodium and steroids) was considered, this proportion decreased to 4.6%. There was not statistical significance (p<0.05) between the use or not of prophylactic regimens in relation to gender, weight, height, asthma severity, hospital admissions, age of onset, age when first evaluated at the outpatient center and household smoking. CONCLUSIONS: The rate of utilization of prophylactic regimens in this population of persistent asthmatic patients was unsatisfactory, a finding particularly stressed by the low rate of subjects on inhaled antiinflammatory drugs. It is necessary to emphasize such measures to face the magnitude that asthma represents in our country.

The Use of Inhaled Corticosteroids in Asthma

Inhaled corticosteroids are the most important therapeutic agents for the pharmacological control of pulmonary inflammation in asthma. There is concern, however, about the occurrence of side effects with the long-term use of inhaled corticosteroids. Because of the potential seriousness of some of these side effects, patients should be monitored carefully and preventively treated for the side effects. Various noncorticosteroid medications have been recommended in guidelines as substitutes for inhaled corticosteroids for daily use as long-term controllers in asthma, e.g., sustained-release theophylline, long-acting beta-agonists, leukotriene modifiers, cromolyn, and nedocromil. However, of the long-term controller medications recommended in the guidelines, only inhaled corticosteroids have to date, been shown clinically to reduce asthma fatalities and to prevent asthma induced lung remodeling.

When Asthma Interrupts Sleep in Children

Nocturnal symptoms of asthma such as coughing, wheezing, dyspnoea and dyspnoea on awakening are common in children with asthma. This is an important issue since nocturnal symptoms may have a negative influence on the child's life, affecting, for example, school performance or quality of life. Only a minority of the patients report their nocturnal symptoms spontaneously. Doctors should therefore specifically ask if a child is experiencing such symptoms. Nocturnal airflow limitation, induced by an increase in inflammatory activity, is thought to be responsible for these symptoms. Several other factors, both endogenous and exogenous, contribute to this fall in lung function. Therapeutic regimens aim to reduce inflammation and the subsequent constriction of the smooth muscle cell. Environmental measures, like smoke avoidance or house dust mite reduction, can reduce the exposure to exogenous triggers, while inhaled medication acts specifically on the inflammation or smooth muscle cell constriction. Treatment with inhaled corticosteroids has a positive influence on lung function and the degree of bronchial hyperresponsiveness. Since short-acting bronchodilators provide dilation for only 4 to 6 hours, their role in the treatment of nocturnal symptoms is less important, especially in children. Long-acting bronchodilators, such as sustained release theophylline, have been shown to improve nocturnal symptoms and (nocturnal) lung function. However, the small therapeutic range of those agents with respect to plasma concentration is a complicating factor for treatment of children with asthma. Long-acting beta(2) agonists have a positive influence on nightly awakenings and lung function. Some studies indicate, however, that the combination of a long-acting beta(2) agonist with an inhaled corticosteroid is superior to long-acting beta(2) agonists alone.

In Vitro Conditions for the Study of the In Vivo Performance of Sustained-Release Theophylline Matrix Tablets Administered in Fasted Conditions and with a High-Fat Diet

Dissolution profiles of theophylline (TP) from three types of sustained-release (SR) matrix tablets (plastic [PL], lipid [LP], and hydrophilic [HP]) in different dissolution media, with and without enzymes, were established. Also investigated was the influence of a treatment of the tablets with peanut oil prior to the dissolution test. The in vivo behavior of the tablets under the fasted state and with the concomitant administration with a high-fat diet was previously evaluated; the diet produced changes in the absorption profiles for the three matrix tablets in comparison with fasted administration. Level A correlations were obtained between cumulative percentage dissolved (CPD) and cumulative percentage absorbed (CPA). For the fasted condition, better correlations were obtained with water as the dissolution medium for the HP and LP matrix; for PL matrix, the best correlation was obtained with a medium with gradual change of pH. The pretreatment with peanut oil showed better correlations for the fed state.

Comparative Pharmacodynamic-Pharmacokinetic Correlation of Oral Sustained-Release Theophylline Formulation in Adult Asthmatics

A sustained-release formulation of theophylline with an innovative release mechanism was evaluated in adult asthmatics. The pharmacodynamics and pharmacokinetic behavior of this formulation was compared with a market formulation (Theobid®). The formulations, each containing 200 mg of anhydrous theophylline, were evaluated in six male subjects, 40–55 years of age, 151–169 cm in height, 41–60 kg in weight, who were nonsmokers with moderate chronic obstructive pulmonary disease (COPD); the study was a randomized, single-dose, open, complete crossover study with an interval of 1 week. Written consent was obtained from the patients prior to the trial. Plasma samples were obtained at 0, 1, 2, 4, 6, 8, 10, and 12 hr postadministration. Pulmonary functions were simultaneously recorded using an Erich Jaeger spirometer. Plasma theophylline assays were performed using high-performance thin-layer chromatography (HPTLC). Individual bioavailability parameters were obtained using the S-Inv computer program. Pharmacodynamic-pharmacokinetic correlation was studied using the Excel 95 version 7.0 Regression Statistics program. The test formulation (innovator) was found to be comparable with the marketed product with respect to tmax, t1/2 and Kel (p <. 05). A significant difference in the means of Cmax and AUC0–12 between the innovator and the market formulation indicated a superior extent of absorption from the innovator formulation. A good pharmacodynamic-pharmacokinetic correlation was observed when plasma theophylline concentration was compared with forced expiratory volume.

Comparative bioavailability of two sustained-release theophylline formulations in the dog

The kinetics of two sustained-release theophylline formulations, Theo-Dur®(Recordati, Milano, Italy) and Diffumal®(Malesci, Firenze, Italy) were studied in eight beagle dogs. In a first part of the study each animal was injected intravenously with aminophylline dihydrate, Aminomal®(Malesci, Firenze, Italy), in order to determine the absolute bioavailability of the two sustained-release theophylline formulations orally administered to the dogs in the second experimental phase, over a period of 9 days, following a balanced two-period cross-over design. Assays for theophylline were performed by high performance liquid chromatography and the pharmacokinetic analysis was performed using the non-compartmental method. The principle of superposition was then applied to predict multiple dose plasma concentrations from experimental single dose data. No significant differences between the two preparations were found with respect to the main pharmacokinetic parameters, showing that the two preparations are bioequivalent. The fact that the differences between experimental and predicted results were not statistically significant allows us to conclude that multiple dose steady state plasma theophylline concentration in the dog can be predicted from experimental single dose data. Furthermore, after repeated treatment, both Diffumal®and Theo-Dur®, given twice daily are able to maintain therapeutic (5–20 mg ml−1) plasma theophylline concentrations in the dog.

Efficacy, tolerability, and effects on quality of life of inhaled salmeterol and oral theophylline in patients with mild-to-moderate chronic obstructive pulmonary disease

The aims of management in mild-to-moderate stable chronic obstructive pulmonary disease (COPD) are to improve symptoms and quality of life (QOL), reduce decline in lung function, prevent and treat complications, increase survival while maintaining QOL, and minimize the adverse effects of treatment. Bronchodilator therapy is the keystone of improving COPD symptoms and functional capacity. The primary objective of this open-label study was to compare the efficacy and tolerability of salmeterol 50 μg BID administered by metered-dose inhaler versus oral, titrated, sustained-release theophylline BID, both given for 3 months to patients with a clinical history of chronic bronchitis. The secondary objectives of the study were to evaluate the safety profile of the two drugs for an additional 9-month period and to assess changes in QOL both within and between treatment groups, using the 36-Item Short Form (SF-36) Health Survey. One hundred seventy-eight outpatients (122 men, 56 women; mean age, 56 ± 12.9 years; mean body weight, 76.1 ± 11.8 kg) were randomized to the two treatment groups. Patients receiving salmeterol showed significant improvement in mean morning peak expiratory flow rate (16.56 L/min) over the 3-month period compared with patients receiving theophylline ( P = 0.02). Salmeterol also significantly increased the percentage of symptom-free days and nights with no additional salbutamol requirement ( P < 0.01). A significant difference was found between increases in forced expiratory volume in 1 second compared with baseline for salmeterol compared with theophylline throughout the initial 3-month period (0.13, 0.16, and 0.16 L at months 1, 2, and 3, respectively) and during the additional 9 months. The incidence of adverse events was similar in the two groups (salmeterol, 49.5%; theophylline, 49.4%), with a lower percentage of pharmacologically predictable adverse events in patients receiving salmeterol (4%) compared with those receiving theophylline (14.8%). Both drugs improved QOL, as measured by effects on the eight aspects of life experience analyzed by the SF-36 questionnaire. Salmeterol therapy was effective in more aspects, and the improvements seen in each were numerically greater than those seen with theophylline therapy. Statistically different changes between the two treatment groups were reported for physical functioning, changes in health perception, and social functioning ( P = 0.02, P = 0.03, and P = 0.004, respectively). These data suggest that inhaled salmeterol 50 μg BID was more effective and better tolerated than oral, titrated theophylline and allowed better long-term control of airways obstruction and symptoms with improved lung function in patients with COPD

The effect of theophylline on blood and sputum eosinophils and ecp in patients with bronchial asthma

It was recently reported that theophylline has an anti-inflammatory and bronchodilating effect on bronchial asthma. Accordingly, to examine the anti-inflammatory effect of theophylline on asthma, especially its effect on eosinophil activation, a sustained-release theophylline preparation (Theolong ®) was administered (daily dose; 400 mg) to 18 patients with mild to moderate bronchial asthma. This was done in order to study the preparations effects on lung function, blood and sputum eosinophils and ECP four weeks pre- and post-administration. Lung function was determined by spirometry and sputum by induced sputum. Blood and sputum ECP levels were determined using an ECP RIA kit. In lung function, there were no differences in vital capacity (VC) or in forced expiratory volume 1 s (FEV 1.0) pre- and post-administration. There were also no differences in the number of blood and sputum eosinophils, but serum and sputum ECP levels decreased. Theophylline is thus expected to exert an inhibitory effect on eosinophil activation and it is suggested as an effective therapeutic drug for bronchial asthma.

Aerosol Beclomethasone Dipropionate Compared With Theophylline as Primary Treatment of Chronic, Mild to Moderately Severe Asthma in Children, by David G. Tinkelman, MD, et al,Pediatrics, 1993;92:64–77

Objective. To compare the benefits and adverse reactions of theophylline and beclomethasone (BDP) in the long-term control of mild to moderate chronic asthma in children.Design. Multicentered, double-blind, double-placebo, randomized, controlled trial.Patients. One hundred ninety-five children between the ages of 6 and 16 years with mild to moderate asthma.Intervention. Treatment with either BDP, 84 μg four times a day, or sustained-release theophylline administered twice daily I doses adjusted for optimum control of symptoms.Main Outcome Measures. Daily diary record of symptoms, peak flow rates, supplemental bronchodilator and glucocorticoid treatment, doctor and hospital visits, absence from work and school, and side effects.Results. Aerosol BDP and sustained-release theophylline were effective primary treatments for mild to moderate chronic asthma. BDP resulted in comparable symptom control with less bronchodilator use and fewer courses of systemic steroids than did theophylline. Side effects were observed significantly more frequently with theophylline than with BDP. Growth velocity suppression was noted with BDP and was more pronounced in boys. Suppression was not associated with alterations in cortisol measurements either at baseline or following stimulation.Conclusions. Both theophylline and BDP are effective therapy for mild to moderate asthma. Caution must be used with the administration of BDP in children because of possible growth velocity suppression.

Parent pointers

Twenty-one patients, 12 to 18 years of age, with nocturnal asthma controlled with sustained-release theophylline administered twice daily, were enrolled in a 10-week, double-blind, two-way crossover study that compared Theo-Dur tablets administered twice daily with an equivalent daily dose of Uniphyl tablets administered once daily at bedtime. Seventeen patients completed the study. The mean morning theophylline serum level obtained with Uniphyl tablets was significantly higher than that obtained with Theo-Dur tablets (13.1 versus 9.6 μg/ml, p = 0.02). The mean evening serum level was significantly lower with Uniphyl tablets (6.3 versus 10.1 μg/ml, p = 0.003). Despite these differences in serum concentrations, morning and evening pulmonary function test values (forced expiratory volume in one second and peak expiratory flow rate) and symptom scores were nearly identical for the two preparations, as was the supplemental use of aerosol bronchodilators. Once-daily dosing with Uniphyl tablets may benefit adolescent patients with nocturnal asthma by increasing compliance and providing better asthma control. In addition, the lower daytime theophylline levels produced by this preparation may also reduce long-term adverse effects on behavior and cognition.

Sustained release theophylline tablets by direct compression: Part 1: formulation and in vitro testing

In an effort to reduce production costs, a simple, direct compression sustained release formulation consisting, principally, of the drug (theophylline) and ethylcellulose was investigated. Ethylcellulose compacts well and also retards drug release. In addition, matrices of this polymer display slow surface erosion which can be enhanced by the incorporation of a swelling agent. This property was utilized in an attempt to decrease the attenuation of the release rate that is observed with matrix tablets that follow the Higuchi pattern of drug release. The release rate decreases because the external layers of the tablet become depleted and water must penetrate the deeper layers of the tablet to reach the remaining drug. The theophylline to ethylcellulose ratio and the tablet hardness were found to influence the rate of drug release. It was possible to sustain the release of a therapeutic dose of theophylline over a 12-h period. Mathematical modeling showed an equally good fit between the data and (a) the Higuchi model, or (b) a model that took into account diffusion, relaxation of the polymer, and erosion. However, the shape of the release curve was altered slightly in those tablets that eroded to a greater extent and residuals analysis illustrated a better fit with the latter model. The erosion mechanism can be used to lessen one of the major problems associated with hydrophobic and plastic matrix tablets, i.e. the continuous reduction in the terminal release rate with time.

In Vitro Release of Theophylline from Poly(Lactic Acid) Sustained-Release Pellets Prepared by Direct Compression

Poly(L-lactic acid), (L-PLA) pellets containing theophylline as a model drug were prepared with increasing bovine serum albumin (BSA) load of 10, 20, 30, 40, or 50% by direct compression. The drug release from pellets was studied in phosphate buffered saline (PBS, pH 7.4) at 37°C. The annealing effect on theophylline release from pellets was also studied at 20, 30, 60, and 80°C. In all cases, release kinetics followed the Higuchian mechanism with an initial burst effect followed by sustained release of theophylline during the experimental period. Increasing BSA load resulted in a linear increase in Higuchian release rates presumably because of the hydrophilic nature of BSA. Furthermore, BSA did not interact chemically with the polymer matrix and was held physically by the dense polymer matrix. However, drug release decreased with an increase in annealing temperature. Release of theophylline was higher from PLA-BSA combination pellets compared to PLA pellets at temperatures below the glass transition temperature (Tg) of the polymer and lower for temperatures above Tg The temperature effect on drug release may be attributed to both the reduction of core solubility in the bulk phase and the lowering of diffusibility of the polymeric membrane. No drug-polymer interactions or polymer degradation was observed within the experimental setup when studied by differential scanning calorimetry (DSC), infrared (FTIR) spectroscopy, and gravimetric methods. DSC studies of pellets showed no hints of microstructural changes (crystallinity) of the polymers. In our experiments, theophylline was released primarily by leaching through channels and not by polymer degradation. The release rate was dependent on BSA loading and annealing. It may be concluded that PLA pellets can be fabricated suitably using BSA and annealing to design sustained-release preparations of water-soluble drugs.

Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma

Background: Inhaled corticosteroids and oral theophylline are effective treatments for moderate asthma. Objective: We sought to compare the benefits and adverse reactions of theophylline and aerosol beclomethasone spray. Methods: A multicenter, double-blind, double-placebo, randomized, controlled trial of 1-year duration was performed. Seven hundred forty-seven patients with asthma received either beclomethasone dipropionate aerosol spray (84 μg four times per day) or sustained-release theophylline twice per day in doses adjusted for optimum control of the disease. The main outcome measures were daily diary of symptoms and peak flow rates (recorded on a mark-sense computer-readable form); supplemental bronchodilator use; doctor's office or hospital visits and absence from work or school; spirometry; methacholine testing; adverse experiences; and cortisol blood measurements. Results: Both treatment strategies reduced symptoms promptly and achieved low absenteeism from work or school and low rates of emergency treatment for asthma. Both maintained nearly normal pulmonary function. Beclomethasone was statistically significantly more effective in reducing symptoms, supplemental bronchodilator and systemic glucocorticoid doses, bronchial hyperresponsiveness, and eosinophilia. However, the magnitude of these differences was small. Theophylline caused more headache, nervousness, insomnia, and gastrointestinal distress, and more patients discontinued treatment because of side effects. Beclomethasone caused more oropharyngeal candidiases and hoarseness and reduced morning plasma cortisol levels before and after cosyntropin. It reduced the rate of growth in children. No new cataracts or glaucoma developed. Conclusion: Theophylline effectively controlled symptoms at lower than the customarily recommended blood level. The risk/benefit profiles of these agents suggest that inhaled corticosteroids may be the preferred agent for most adult patients and for some children. (J Allergy Clin Immunol 1998;101:14-23.)

Effect of once daily and twice daily sustained release theophylline formulations on daytime variation of bronchial hyperresponsiveness in asthmatic patients.

BACKGROUND: Previous studies evaluating spirometric values and symptoms have shown that once daily theophylline administered in the evening produces greater stabilisation of the airway function in asthmatic patients than the...

Development of sustained release theophylline pellets coated with calcium pectinate

We have produced cores containing theophylline, calcium acetate and microcrystalline cellulose by extrusion-spheronization and then applied a coating of calcium pectinate by interfacial complexation. After drying, the coatings were observed by scanning electron microspcopy to be 50–80 μm thick. The type of pectin used, the core size and the coating time all influenced the yield of theophylline in the coated cores. Theophylline release from the uncoated cores was rapid and linear with the square root of time. The in-vitro release of theophylline from the coated cores was tested in water, simulated gastric fluid USP minus pepsin (SGF) and a Tris buffer (pH 7.4). In general, release was essentially constant until 75–80% of the drug was released. The large coated cores released over a period of about 4 h and the small coated cores released over a period of 2 h. Although the coatings swelled more when they were rehydrated in the Tris buffer compared to water and SGF, theophylline release was similar in all the dissolution media. In particular, release was not increased by SGF as may have been expected from studies using a similar polysaccharide sodium alginate. Calcium pectinate coatings are easy to apply, do not require harsh conditions and may yield release profiles which are relatively independent of pH.

Microencapsulation of theophylline using ethylcellulose: In vitro drug release and kinetic modelling

This study details the process of coating theophylline with ethylcellulose using the coacervation technique of microencapsulation. Microencapsulation of the phylline not only renders it sustained-release, but also decreases its gastric irritation and masks the bitter taste (Lin and Yang 1987). The non-solvent addition method was chosen through a literature survey to ascertain various phases of the coacervate (Robinson 1989, Nixon and Wong 1990). A three-phase diagram was used to determine the optimum quantity of each component required. Steps were then carried out to optimize the production. Drug release rates of the prepared microcapsules were determined over 12-h cycles using the U.S.P. dissolution apparatus and the results obtained were compared with those of Knoll's (Germany) sustained-release theophylline capsules. Significant con trol over the rate of drug released from the developed dosage form was achieved during the experiment time (12 h). It is concluded that the method employed in this study could be effectively used in the preparation of sustained-release theophylline microcapsules capable of releasing their drug content for an extended period of time. Kinetic studies suggested that both the prepared microcapsules and Knoll's product followed Higuchi's model for drug release. Particle size and release data analysis from five consecutive batches prepared in the laboratory indicated suitable reproducibility of the coacervation process.

生体リズムにあわせたＴｈｅｏｐｈｙｌｌｉｎｅ投与法とＲｏｕｎｄ‐Ｔｈｅ‐Ｃｌｏｃｋ療法の臨床効果の比較

Depending on the administration method, the highly effective therapeutic concentrations (VSC: variable serum concentration) of theophylline can be attained only in the time range of frequent asthma attack. We used an oral sustained-release theophylline preparation in seven patients with bronchial asthma (2 males and 5 females ; mean age: 38.7 years) who had required more than 3 admissions per year, because of bronchial asthma attack despite being treated with Round-The-Clock (RTC) therapy of theophylline and inhalation of steroid. We examined the annual frequency of admissions and the.peak expiratory flow rate (PEFR) in remission.Even though no difference was noted in serum concentrations of theophylline in the morning (the time range of attack) between RTC therapy and VSC therapy, the mean number of admissions during VSC therapy was 1.14 compared to 3.86 recorded during RTC therapy (p<0.001). PEFR in remission showed a significant improvement with VSC therapy compared to PEFR recorded during RTC therapy (p<0.05).VSC therapy was proven to be useful for patients who failed to attain a favorable control of asthma attack by RTC therapy.

In Vivo Bioavailability of a Multiparticulate Matrix Sustained-Release Theophylline Preparation Under Fed and Fasted Conditions

The in vivo bioavailability of a novel multiparticulate matrix sustained-release theophylline preparation was compared under fed and fasted conditions. Twelve healthy volunteers participated in the study conducted according to a randomized, two-way crossover design. The parameters used for the comparison were: total area under the serum concentration-time curve (AUC0), time to reach peak serum concentration (Tmax), and peak serum concentration (Cmax). No statistically signifcant difference was observed bemeen the fed and fasted logarithmic transformed values of AUCG0 and Cmax as well as the fed and fasted values of Tmax In addition, the 90% confidence interval for the ratio of logarithmic transformed AUC0 values of the fed condition over those of the fasted was calculated to lie between 0.90 and 1.04, which is within the bioequivalence limit of 0.80–1.25. These findings indicate that both the rate and extent of absorption of the novel preparation were not significantly affected by food, although a lag time in absorption was observed in the fed condition

Maternal theophylline administration and breathing movements in late-gestation human fetuses

To investigate the relation between maternal administration of theophylline and breathing movements during late gestation in human fetuses. After a 1-hour control period, 17 women with normally grown fetuses at 33-38 weeks' gestation were given 400 mg of sustained-release theophylline orally. Maternal plasma theophylline and glucose concentrations were measured every hour, and the incidence of fetal breathing movements and breathing rates were measured continuously during the next 8 hours. Results were compared with those of a similar control group that did not receive theophylline. The maternal plasma theophylline concentration increased to detectable levels after 1 hour, reached therapeutic levels of 6.9 +/- 0.4 micrograms/mL (standard error of the mean) after 6 hours, and thereafter averaged 8.3 +/- 0.3 micrograms/mL, significantly higher than initial control values (P < .05). The mean glucose concentration was unchanged during the first 6 hours (79.2 +/- 1.1 mg/dL) and then decreased somewhat, averaging 75.8 +/- 1.1 mg/dL in the 7-8 hour period. The incidence of fetal breathing increased 26.4 +/- 1.9% after 5 hours and remained elevated during the next 3 hours at levels significantly higher than in the initial control period (P < .05) and higher than in the control group that did not receive theophylline. The mean hourly breathing rate averaged 40.9 +/- 1.3 breaths per minute after ingestion of theophylline, a nonsignificant change. Ingestion of theophylline by pregnant women in late gestation is associated with an increase in fetal breathing movements. Theophylline has been used widely in the management of asthma in pregnancy, and the assessment of fetal breathing movements is used routinely for evaluation of fetal status. Therefore, account must be taken of changes in breathing movements caused by maternal theophylline administration.