Theophylline Therapy Research Articles

PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP

PDE7A is a recently described 3′,5′-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) whose expression has been detected in T-cells. As treatment with the methylxanthine theophylline, a nonspecific PDE inhibitor, induces apoptosis in leukemic cells from patients with the B-lineage malignancy chronic lymphocytic leukemia (CLL), we sought to determine if PDE7A was a target of theophylline therapy in such cells. Western analysis revealed expression of PDE7A in normal human splenic B-cells, primary CLL cells, and in a CLL-derived cell line (WSU-CLL). Among the six cAMP PDEs (PDE1B, PDE3B, PDE4A, PDE4B, PDE4D, and PDE7) examined in WSU-CLL, only PDE7A levels were augmented by treatment with methylxanthines. The activity of PDE7A isolated from the WSU-CLL cell line by immunoprecipitation was inhibited by theophylline and IBMX with IC 50 values of 343.5 and 8.6 μM, respectively. WSU-CLL PDE7A was also up-regulated by a novel specific inhibitor (IC242), which inhibits PDE7A from WSU-CLL cells with an IC 50 value of 0.84 μM. IC242-mediated up-regulation of PDE7A was blocked by the protein kinase A (PKA) inhibitor H-89.

Reassessment of Theophylline Use for Severe Asthma Exacerbation: Is It Justified in Critically Ill Hospitalized Patients?

In the 1990s, numerous double-blind, randomized, placebo-controlled trials revealed that theophylline therapy offered no benefit to inhaled beta2 agonists and systemic corticosteroids in the treatment of patients hospitalized for asthma exacerbations. Routine use of theophylline in patients hospitalized for asthma is no longer advocated due to the potential for serious adverse effects and lack of benefit. However, the question remains whether this drug adds any benefits in critically ill patients who are being admitted to an intensive care unit. Two recent pediatric studies suggest that theophylline therapy may have a role in the management of patients with impending respiratory failure who have failed aggressive treatment with inhaled beta2 agonists, systemic corticosteroids, and inhaled ipratropium. If a patient has failed to respond adequately to high-dose routine therapies, theophylline should be initiated by a clinician who is competent in dosing, monitoring serum concentrations, and assessing factors that modify clearance of this high-risk drug. Further clinical research is needed to verify the value of theophylline in adults and children with severe asthma exacerbations and impending respiratory failure.

Pacemaker Therapy for Sleep Apnea Syndrome

Sleep apnea syndrome (SAS), characterized by frequent episodes of apnea or hypopnea during sleep, affects more than 10% of people older than 65. Treatments with nasal continuous positive airway pressure, theophylline, or surgical ablative therapy have notable drawbacks. These researchers found that SAS patients with pacemakers fared better during nights when their devices were in atrial overdrive. Of 47 pacemaker patients with symptoms suggestive …

Nocturnal asthma uncontrolled by inhaled corticosteroids: theophylline or long-acting beta2 agonists?

Asthma is an inflammatory disease of the airways that is frequently characterised by marked circadian rhythm. Nocturnal and early morning symptoms are quite common among patients with asthma. Increased mortality and decreased quality of life are associated with nocturnal asthma. Although numerous mechanisms contribute to the pathophysiology of nocturnal asthma, increasing evidence suggests the most important mechanisms relate to airway inflammation. According to international guidelines, patients with persistent asthma should receive long term daily anti-inflammatory therapy. A therapeutic trial with anti-inflammatory therapy alone (without a long-acting bronchodilator) should be assessed to determine if this therapy will eliminate nocturnal and early morning symptoms. If environmental control and low to moderate doses of inhaled corticosteroids do not eliminate nocturnal symptoms, the addition of a long-acting bronchodilator is warranted. Long-acting inhaled beta2 agonists (e.g. salmeterol, formoterol) are effective in managing nocturnal asthma that is inadequately controlled by anti-inflammatory agents. In addition, sustained release theophylline and controlled release oral beta2 agonists are effective. In patients with nocturnal symptoms despite low to high doses of inhaled corticosteroids, the addition of salmeterol has been demonstrated to be superior to doubling the inhaled corticosteroid dose. In trials comparing salmeterol with theophylline, 3 studies revealed salmeterol was superior to theophylline (as measured by e.g. morning peak expiratory flow, percent decrease in awakenings, and need for rescue salbutamol), whereas 2 studies found the therapies of equal efficacy. Studies comparing salmeterol to oral long-acting beta2 agonists reveal salmeterol to be superior to terbutaline and equivalent in efficacy to other oral agents. Microarousals unrelated to asthma are consistently increased when theophylline is compared to salmeterol in laboratory sleep studies. In addition to efficacy data, clinicians must weigh benefits and risks in choosing therapy for nocturnal asthma. Long-acting inhaled beta2 agonists are generally well tolerated. If theophylline therapy is to be used safely, clinicians must be quite familiar with numerous factors that alter clearance of this drug, and they must be prepared to use appropriate doses and monitor serum concentrations. Comparative studies using validated, disease specific quality of life instruments (e.g. Asthma Quality of Life Questionnaire) have shown long-acting inhaled beta2 agonists are preferred to other long-acting bronchodilators. Examination of costs for these therapeutic options reveals that evening only doses of long-acting oral bronchodilators are less expensive than multiple inhaled doses. However, costs of monitoring serum concentrations, risks, quality of life and otheroutcome measures must also be considered. Long-acting inhaled beta2 agonists are the agents of choice for managing nocturnal asthma in patients who are symptomatic despite anti-inflammatory agents and other standard management (e.g. environmental control). These agents offer a high degree of efficacy along with a good margin of safety and improved quality of life.

Efficacy of Inhaled Budesonide and Oral Theophylline in Asthmatic Subjects

The aim of present study was to evaluate clinical, functional, and anti-inflammatory effects of inhaled budesonide and oral theophylline treatments in patients with mild to moderate asthma. The study included 38 patients. After a 10-day run-in period, the patients were randomly assigned into two groups. Group 1 received inhaled budesonide (Pulmicort Turbuhaler) 800 μg/day for 4 weeks. Group 2 received oral theophylline (Talotren tablets, 200 mg twice daily) for 4 weeks. Inhaled budesonide therapy was accompanied by a significant decrease in serum interleukin (IL)-5 levels (p < 0.0005) and blood, sputum, and nasal eosinophil counts (p < 0.005). It produced a significant reduction in daytime (p < 0.01) and nighttime (p < 0.005) symptom scores and an increase in morning (p < 0.005) and evening (p < 0.05) peak expiratory flow (PEF) and forced expiratory volume in 1 sec (FEV1) values (p < 0.01). Theophylline therapy was associated with a significant decrease in blood (p < 0.02) and nasal (p < 0.01) eosinophil counts and serum IL-5 levels (p < 0.01). It resulted in significant improvements in daytime and nighttime symptom scores (p < 0.05), and morning PEF and FEV1 values (p < 0.05). These changes were more significant in group 1 than in group 2. There was no statistically significant difference between the two groups with respect to post-treatment values. Our results confirm the role of inhaled corticosteroids in the treatment of asthma and are consistent with the recommendation that theophylline exerts an anti-inflammatory effect. Further studies should be conducted to determine long-term benefits of theophylline.

Hypomagnesaemia in chronic, stable asthmatics: prevalence, correlation with severity and hospitalization.

Magnesium (Mg) deficiency is associated with airway hyperreactivity, wheeze and impairment of lung function. The prevalence of hypomagnesaemia, and its effect on asthma is unclear. Therefore, this prospective study was undertaken to evaluate the prevalence of low serum Mg level, to correlate whether hypomagnesaemia (serum Mg level <0.74 mmol x L(-1)) is associated with severity of asthma and increased frequency of hospitalizations in chronic, stable asthmatics. Ninety-three chronic stable asthmatics, who were on regular follow-up in an asthma clinic, were studied. On attendance to the asthma clinic, each subject was interviewed and clinically evaluated. The serum Mg level (normal 0.74-1.2 mmol x L(-1)), as well as the severity of asthma was measured. The medications used were recorded. The total number of hospitalizations due to asthma exacerbation was scored for the last three months that preceded the date of measuring the serum Mg level. Twenty-five patients (27%) had a low Mg level with a mean+/-SD of 0.69+/-0.04 mmol x L(-1), while 68/93 (73%) had a normal Mg level (0.82+/-0.08 mmol x L(-1)). The number of hospitalizations in asthmatics with low Mg levels was 10/25 (40%), compared to 8/68 (12%) (p<0.01) in asthmatics with normal Mg levels. Multiple logistic regression analysis showed that severe asthma was the only factor associated significantly with hypomagnesaemia (p=0.04). No effect was observed for inhaled beta-agonist, inhaled steroid or theophylline therapy on serum Mg level. To conclude, hypomagnesaemia is common in chronic asthmatics. Chronic asthmatics with low Mg tend to have more hospitalizations than chronic asthmatics with normal Mg. Hypomagnesaemia was also associated with more severe asthma.

Methylxanthines and sensorineural outcome at 14 years in children < 1501 g birthweight.

Methylxanthines, including theophylline, have been used extensively and successfully to treat apnoea in preterm infants. However, long-term consequences of such therapy are largely unknown. The aim of this study was to determine the relationship between theophylline therapy and outcome at 14 years of age in surviving preterm children of birthweight < 1501 g. The subjects of this study were 154 consecutive survivors with birthweights < 1501 g born from 1 October 1980 to 31 March 1982; 130 (84.4%) were assessed at 14 years of age. Outcomes included motor function, psychological test scores, and growth. Of the 130 children assessed, 69 (53.1%) had been exposed to theophylline; 13.0% had cerebral palsy, significantly higher than 1.6% in the 61 children not exposed to theophylline (P < 0.02). This difference remained statistically significant after adjusting for potential confounding variables including the presence of cerebroventricular haemorrhage. In contrast, after adjusting for known confounding variables, children who had received theophylline achieved higher psychological test scores. There was no association between theophylline therapy and growth. Theophylline therapy in the newborn period is associated with some evidence of harmful, but also helpful sensorineural effects at 14 years of age.

A review of clinical use of theophylline in acute asthma: factors influencing kinetic disposition and drug interactions.

The clinical use of theophylline as a first line bronchodilator has declined during the last two decades. However, many therapeutic mechanisms for bronchial asthma have been discovered, and recent studies have suggested that theophylline therapy can play a beneficial role in the management of both chronic stable asthma and exacerbated disease treated in the emergency setting. In this article, the author describes the pharmacokinetics of theophylline and the major factors that influence the kinetics of the drug, such as physiopathological conditions and interactions with concomitantly administered drugs. Practical guidelines are then given on how to achieve optimal serum levels when planning theophylline therapy, including use of nomograms to decide loading and maintenance doses for nonsmoking adult asthmatic patients and adjustments for asthmatic patients with complications or on other drugs that may alter the kinetic disposition of theophylline.

Spontane intrakranielle Hypotension: Eine seltene Ursache für chronische Kopfschmerzen

Spontaneous intracranial hypotension is a rare cause of chronic postural headache. We report the case of a 58-year-old woman with a 1.5 year history of chronic headache in upright position, nausea and vomiting. Neurological examination was normal. The Gd-enhanced MRI of the brain showed an abnormal meningeal enhancement over the cerebral convexity. The CSF was normal. Opening pressure during lumbar puncture was 6 cm H2O in the lateral recumbent position. No evidence of underlying systemic, infectious or neoplastic diseases could be detected. The headache was alleviated under theophylline therapy. Spontaneous intracranial hypotension should be considered in the differential diagnosis of chronic postural headache. MRI revealing meningeal enhancement and low opening pressure in lumbar puncture are important findings for the diagnosis of spontaneous intracranial hypotension.

EVALUATION OF THE EFFECT OF LOW-DOSE ORAL THEOPHYLLINE THERAPY ON SOME BONE TURNOVER MARKERS AND SERUM PROLIDASE I ACTIVITY IN MILD ASTHMATICS

Hypercalcemia and hypercalciuria observed both in humans and in animals who were on long-term theophylline therapy, prompted us to investigate whether oral theophylline treatment at optimal doses causes any adverse side effects on bone metabolism in mild asthmatics. Therefore, serum osteocalcin (BGP) and total alkaline phosphatase (TALP, EC 3.1.3.1) as bone formation markers, serum prolidase I (EC 3.4.13.9) activity as a marker for collagen metabolism, urinary deoxypyridinoline (Dpd), hydroxyproline (Hyp) and fasting urinary calcium as bone resorption markers, were measured in 18 mild asthmatics who had been treated with theophylline over 1–10 years. Among measured bone turnover markers, BGP, TALP, and Hyp levels were found to be increased in mild asthmatics; and BGP showed the greatest percent mean increase (98%) over the healthy subjects. However, these increments did not exceed the upper reference limits. Serum prolidase I activity was also increased in mild asthmatics receiving theophylline. Our results indicate that theophylline therapy at optimal doses may not exert adverse side effects on bone homeostasis, but patients receiving supratherapeutic doses of theophylline should be under close examination in order to predict future bone mass status. 1999 Academic Press@p$hr

A Drug Interaction Between Zafirlukast and Theophylline

Katial RK, Stelzle RC, Bonner MW, Marino M, Cantilena LR, Smith LJArch Intern Med.158199817131715The apparent low adverse effect profile of the new drug zafirlukast has made it an attractive choice in the treatment of asthma. This study describes the first case of a potentially serious drug-drug interaction between zafirlukast and theophylline.A 15-year-old white girl with asthma had been taking theophylline (Slo-bid, Rhone-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) (300 mg twice daily), with drug levels of approximately 61 micromol/L (11.0 μg/mL) for several years. Recently, her serum theophylline levels had increased to the toxic range (133.2 μL/L [24 μg/mL]) shortly after the addition of zafirlukast (Accolate, Zeneca Pharmaceuticals, Wilmington, Del) to her regimen. Attempts were made to stop and then restart the theophylline therapy at progressively lower doses; however, with each attempt, the patient's reaction to the drug became more toxic, with serum theophylline levels ranging between 99.9 and 149.9 μg/L (18 and 27 μg/mL). So this potential drug-drug interaction could be investigated, the patient stopped taking both drugs for 1 week. Then, she again started taking theophylline (75 mg twice daily), and over 2 days reached a steady state serum theophylline level of 12.8 to 14.4 μL/L (2.3–2.6 μg/mL). On the third day, zafirlukast (20 mg twice daily) was reintroduced to the regimen, and the theophylline therapy was continued. By the fifth day, a dramatic sevenfold increase was seen in the serum theophylline level (101.6 micromol/L [18.3 μg/mL]). The areas under the curve for theophylline alone and theophylline with zafirlukast were 29.3 and 197 (mg × h)/L, respectively.One explanation for the noted increase in the theophylline level is that metabolism occurs mainly by cytochrome P450 (CYP 1A2), an enzyme that is known to be inhibited with high concentrations of zafirlukast. Although the current metabolism of the two drugs in combination is poorly understood, the potential for serious interactions seems to exist in the rapidly growing population of persons with asthma, for whom they may be prescribed. The noted increase in the theophylline level after zafirlukast administration is in contrast to the original reports by the manufacturer. Therefore, we recommend that physicians evaluate serum theophylline levels closely when prescribing the two drugs in combination.The initial report I read suggested that theophyllinedecreased serum concentrations of zafirlukast (Medical Letter. 1996;38:111) Zafirlukast also inhibits CYP3A4, which catalyzed the metabolism of corticosteroids. Zileuton is also metabolized by cytochrome P450, and can markedly increase serum concentrations of theophylline. Montelukast has fewer drug interactions than either zafirlukast or zileuton. In vitro studies indicate that montelukast does not inhibit CYP-450 enzymes. Clinical studies indicate that the drug does not interact with theophylline (Malmstrom,Am J Ther. 1998;5:189) or prednisone.

Efficiency of Continuous Positive Airway Pressure versus Theophylline Therapy in Sleep Apnea: Comparative Sleep Laboratory Studies on Objective and Subjective Sleep and Awakening Quality

Sleep apnea is the most common sleep-related breathing disorder characterized by repetitive episodes of hypoxemia. Therapies include behavioral, surgical, orthodontic, pneumological, and pharmacological interventions. The aim of the present study was to compare the efficiency of pneumological therapy by nasal continuous positive airway pressure (CPAP) versus a pharmacological approach with theophylline (Respicur retard^® 400 mg) on respiratory variables as well as objective and subjective sleep and awakening quality in patients with moderate sleep apnea measured by polysomnography and psychometry. Under CPAP therapy all respiratory variables improved and normalized, while under theophylline only the apnea-hypopnea index and the desaturation index improved but still did not return to normal values. Regarding sleep initiation and maintenance, CPAP therapy prolonged sleep latency and reduced movement time, while patients treated with theophylline showed reduced total sleep period, total sleep time and sleep efficiency. Sleep architecture demonstrated an increase in deep sleep and REM stages under CPAP therapy, and remained unchanged under theophylline. Concerning subjective sleep and awakening quality, both treatments improved well-being in the morning. Regarding objective awakening quality, reaction time performance was improved in both groups. In conclusion, CPAP treatment is more effective than theophylline regarding respiratory variables as well as the normalization of sleep maintenance and sleep architecture in sleep apnea patients.

Population pharmacokinetic analysis of theophylline: relationship between serum concentrations and clinical effects in therapeutic drug monitoring

Therapeutic drug monitoring (TDM) of theophylline is essential duties at hospital pharmacy in Japan. The relationship between serum concentrations and clinical effects of theophylline has been investigated. The pharmacokinetics of theophylline was determined from the concentration of theophylline in the serum which were calculated on the basis of TDM for patients administered theophylline. The one-compartment model as a pharmacokinetic model was assumed. The relationship between clinical effects of theophylline and the predicted concentrations calculated using population parameters was evaluated. The obtained parameters are ka(h-1) = 0.223, ke(h-1) = 0.047 (1-0.0025.age(y) (p.o.) and 0.076(1-0.0025.age(y)) (d.i.v.), Vd(1/kg) = 0.733 (p.o.) and 0.830 (d.i.v.). The bioavailability is 0.732, and theophylline/aminophylline is 0.846. The model including no serum creatinine as a variational factor was considered to be best. The following three groups were used as a clinical evaluation; effective as theophylline therapy was 43%, no change of the clinical status after administration of theophylline was 42%, and aggravation after administration of theophylline was 15%. There is no relationship between the predicted concentration using parameters of the final model and these three groups. These results suggest that TDM of theophylline should be assessed in terms of clinical effects and also suggests that in should be kept monitoring from the viewpoint of the prevention of toxic effects in the theophylline therapy.

Theophylline for Irreversible Chronic Airflow Limitation: A Randomized Study Comparing n of 1 Trials to Standard Practice

To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice. Randomized study of n of 1 trials vs standard practice. Outpatient departments in two tertiary care centers. Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N=34) or standard practice. The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization. The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, -2.8; 95% confidence limits [CLs], -8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, -4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, -26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment. Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usa e, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice.

Controlled-Release Hydrophilic Tablets for Individualized Theophylline Therapy

Directly compressible controlled-release (CR) theophylline tablet formulations with a non-zero-order drug release were prepared using various grades of Methocels®. These tablet formulations were employed in the individualization of therapy with the aid of a pharmacokinetic simulation model developed with STELLA®II computer software. In vitro drug release data were used to simulate plasma concentration-time (C,t) profiles based on a wide range of previously reported patient pharmacokinetic parameters (clearances of 2–5 L/hr and apparent volumes of distribution of 20–50 L). The simulations indicated that formulations containing low-viscosity Methocels (E4, K4, and K4CR) were suitable for individualizing theophylline therapy. Average steady-state concentrations were well within the therapeutic range of 10–20 μg/ml. High-viscosity polymers such as E10CR, K15, and K15CR yielded subtherapeutic concentrations and were deemed unsuitable. Thus, a pharmacokinetic simulation program capable of predicting in vivo C,t profiles (even though theophylline release occurred by a non-zero order) may be useful for individualizing theophylline therapy that involves CR formulations.

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

Effect of Single Dose Theophylline on Middle Cerebral Artery (Mca) Blood Flow Velocity (Bfv) in Very Low Birth Weight (Vlbw) Infants † 988

It has been suggested that theophylline therapy reduces cerebral BFV in preterm infants, possibly related to hypocarbia. In order to determine the effect of a single dose of intravenously administered theophylline on MCA BFV, we studied 8 preterm infants (mean b.w. 1005±195 grams; mean g.a.28±1.9 weeks; mean postnatal age 2.75±0.9 days) who were being weaned from a ventilator. The MCA Doppler BFV, cardiac output, mean arterial pressure (MAP), heart rate (HR), and arterial blood gases (ABG) were recorded before, at 1 hour, and 15 hours after a 30 minute IV infusion of 5mg/kg of theophylline. The relative vascular resistance (VR) was calculated using the ratio of MAP to mean BFV (Vmean). Serum theophylline levels were obtained at 1 hour and 15 hours after administration. Results: values in mean± SD. Table

Effect of Theophylline on Erythrocytosis in Chronic Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease (COPD) tend to develop secondary erythrocytosis to compensate for their chronic hypoxia. Theophylline has recently been shown to reduce hematocrit and erythropoietin blood levels in normal subjects and in patients with erythrocytosis after renal transplantation. To determine whether theophylline may be used to lower the hematocrit in patients with COPD. Two hundred four patients with COPD were studied retrospectively and 10 patients prospectively (8 starting treatment with the drug [group 1] and 2 who suspended its long-term use [group 2]) for the correlation between theophylline therapy and hematocrit and erythropoietin level. In the patients studied retrospectively, lower hematocrits were found in the theophylline-treated than in the untreated patients (0.43 +/- 0.006 vs 0.46 +/- 0.007, respectively; P < .002). Twelve untreated patients and 2 of those treated with theophylline had hematocrits above 52%. Oxygen saturation levels were similar in both groups, and exclusion of patients with oxygen saturation lower than 88% did not change the pattern, suggesting that the effect of theophylline could not be entirely explained by improved oxygen availability. Seven of the 8 patients studied prospectively in group 1 (P < .02) and the 2 patients in group 2 showed inverse correlations between hematocrits and theophylline administration. A similar pattern was observed with serum erythropoietin levels in 5 of 7 patients studied. The effects were reproducible on rechallenge in 3 of the 4 patients in group 1 and the 2 patients in group 2. Theophylline may have a beneficial effect in treatment and prevention of erythrocytosis in patients with COPD.

Theophylline revisited.

For over 50 years, theophylline has been used regularly for the management of chronic asthma. However, because of its perceived narrow therapeutic index and the fact that it has been considered a weak bronchodilator, the use of theophylline therapy has diminished. Furthermore, with the introduction of newer pharmacologic agents and recommendations in widely accepted guidelines, both nationally and internationally, have further contributed to its decreased use. For years, theophylline has not only been considered a bronchodilator, but for many clinicians, an agent that could be used to enhance respiratory muscle function and mucociliary clearance and act at the level of the central nervous system to enhance ventilation. These properties were felt to be potentially useful for patients with severe exacerbated asthma. Recent studies have suggested that theophylline therapy can play a beneficial role in the management of both chronic stable asthma and exacerbated disease treated in the emergency department setting. Furthermore, a growing body of evidence suggests that theophylline has certain antiinflammatory and immunomodulating properties, even at plasma concentration levels below the accepted therapeutic range. If this is true, then theophylline may act best as a controller medication in the management of asthma. Because of its low cost and its ease of administration, theophylline therapy should be revisited and discussed as not only a reliever of bronchospasm, but a controller of chronic asthma.

Monitoring theophylline therapy to prevent toxicity

Monitoring theophylline therapy to prevent toxicity