Slow-release Theophylline Preparation Research Articles

Suppression of Airway Inflammation by Theophylline in Adult Bronchial Asthma

Background: Chronic continuous airway inflammation caused by eosinophils has been noted to play critical roles in the pathophysiology of bronchial asthma, in addition to reversible obstruction and hypersensitivity of the respiratory tract. Therefore, suppression of chronic airway inflammation has become more important in asthma treatment. Although theophylline has been a conventionally used bronchodilator, it has been recently reported to have concurrent anti-inflammatory effects. Objective: Accordingly, we studied the effects of a slow-release theophylline preparation, Theolong^®, on airway inflammation. Methods: Administration of Theolong 400 mg/day to 24 patients with mild or moderate asthma and measuring eosinophil cationic protein (ECP), a marker of airway inflammation, and eosinophils in sputum and peripheral blood at 4 and 8 weeks. Results: As a result, sputum ECP, serum ECP and sputum eosinophil count (%) were significantly lowered after 4 and 8 weeks. Conclusion: Thus, in the theophylline-administered group, slow-release theophylline, Theolong^®, was effective in treating asthma, with anti-inflammatory effects on inflammatory cells besides its bronchodilator action.

The pharmacokinetics of a slow-release theophylline preparation in horses after intravenous and oral administration.

The pharmacokinetics of a slow-release theophylline formulation was investigated following intravenous and oral administration at 10 mg/kg in horses. A tricompartmental model was selected to describe the intravenous plasma profile. The elimination half-life (t1/2 beta) was 16.91 +/- 0.93 h, the apparent volume of distribution (Vd) was 1.35 +/- 0.18 L/kg and the body clearance (ClB) was 0.061 +/- 0.009 L kg-1 h. After oral administration the half-life of absorption was 1.24 +/- 0.30 h, and the calculated bioavailability was above 100%. The t1/2 beta after oral administration was 18.51 +/- 1.75 h, only a little longer than that after intravenous administration. The slow release formulation did not exhibit any advantage in prolonging the t1/2 beta of theophylline in the horse.

Circadian variation in theophylline absorption during chronic dosing with a slow release theophylline preparation and the effect of clock time of dosing.

1. Eight volunteers were given seven doses of 200 mg of slow release theophylline at either 11.00 h and 23.00 h (regimen 1) or 17.00 h and 05.00 h (regimen 2). At the time of the sixth dose (60 h) hourly blood sampling was started and continued for 24 h. After at least 1 week volunteers crossed over to the other regimen. 2. Volunteers retired to bed at 23.00 h and arose after the 07.00 h sample during both regimens. 3. During regimen 1 there was a marked rise in mean tmax from 3.3 h after dosing at 11.00 h to 9.3 h after dosing at 23.00 h (P less than 0.001). There was also a fall in AUC(0,12) from 89.9 mg l-1 h after dosing at 11.00 h to 79.0 mg l-1 h after dosing at 23.00 h. There was no difference in mean Cmax values. 4. During regimen 2 these circadian changes were abolished with mean values after both dosing times lying between those observed during regimen 1. 5. A marked delay in absorption occurs at night and cannot be explained by food intake.

Effect of theophylline on gastroesophageal reflux in patients with asthma

A possible role of methylxanthines in the high incidence of gastroesophageal reflux (GER) in patients with asthma has been suggested. Therefore, we used a randomized, double-blind, crossover design to compare the effects of a 1-week conventional theophylline treatment and a 1-week placebo treatment in 16 adult patients with asthma. No oral or parenteral glucocorticoids were administered, but seven patients were taking inhaled corticoids. All patients needed inhaled adrenergic drugs. At the end of each period of theophylline or placebo treatment, the patients were carefully questioned with respect to respiratory and digestive symptoms, forced expiratory flows were measured, and GER was assessed by prolonged nocturnal intraesophageal pH monitoring. Peak expiratory flow was measured three times a day throughout the study. No significant increase in GER was found with theophylline compared to placebo, and forced expiratory flows improved with theophylline ( p < 0.05 for FEV 1 and p < 0.01 for peak expiratory flow rate). There was no correlation between GER, the duration of asthma, and forced expiratory flows. Thus, our study failed to demonstrate any adverse effect of a slow-release theophylline preparation on GER in patients with asthma. These results further suggest that the presence of GER is not a contraindication to the use of a slow-release theophylline in subjects with asthma.

USING SALIVA TO MONITOR THEOPHYLLINE THERAPY.

The authors measured theophylline concentrations in 137 paired blood and saliva specimens obtained from 68 children, aged 2 months to 14 years, who were treated with oral slow-release theophylline preparations, and from …

The influence of food on the bioavailability of a slow release theophylline preparation.

Food-induced changes in the absorption of Theostat 300, a controlled release formulation of theophylline, have been studied in healthy volunteers. This open, randomised, 3-way, single-dose study involved 12 volunteers who received the drug either while fasting, or with a standardised low-fat (10g), or high-fat (60g) breakfast. Each subject was studied over a 3-week period, with 3 separate days of oral treatment and a 7-day washout period between treatments. The results showed no differences in AUC0-24 and tmax values between the 3 kinds of diet. The only differences observed concerned absorption. Food intake increased Cmax values by 20%. The steady-state peak concentration obtained by means of simulated plasma levels was not influenced by food intake. This slight food-drug interaction of Theostat 300 seemed to be of no clinical significance.

Absorption characteristics of once-a-day slow-release theophylline preparation in children with asthma

The single- and multiple-dose absorption characteristics of a new sustained-release theophylline preparation, which has been formulated for once per day dosing in adults, were investigated in children aged 8 to 14 years. Four single doses were studied, each dose separated by 1 week. During steady state the preparation was given once daily in the morning for 1 week, and serum theophylline concentration was determined through two dosing intervals (48 hours). The product showed excellent sustained-release characteristics and consistent absorption profiles, which were not affected to any clinically important extent by the intake of various meals. After single doses, only 77% to 91% of the product was absorbed during the first 28 hours after dosing. However, bioavailability was complete both after single doses and during steady state. Eight of 14 children had steady-state fluctuations in serum theophylline levels of less than 90% when given doses once daily. Steady-state day-to-day variations in serum theophylline profiles were small in all patients except one, in whom differences up to 33 mumol/L (6 micrograms/mL) were seen (8 hours after dosing). We conclude that this formulation is completely absorbed at a sufficiently slow and consistent rate to permit acceptable fluctuations in absorption with once daily dosing for many, but not all, patients. However, it should not be used in very young children until bioavailability has been studied in this age group.

徐放性Ｔｈｅｏｐｈｙｌｌｉｎ製剤の投与方法の検討 ぜん息発作期並びに寛解期の体内動態の比較

徐放性Ｔｈｅｏｐｈｙｌｌｉｎ製剤の投与方法の検討 ぜん息発作期並びに寛解期の体内動態の比較

The pharmacokinetics of uniphyllin in nocturnal asthma

Three consecutive doses of approximately 10 mg/kg of a once daily slow-release theophylline preparation (Uniphyllin) were given at 22.00 hours to 15 patients with nocturnal asthma who were recovering from an acute exacerbation of their asthma. Twenty-four hour plasma theophylline profiles were obtained after the first and third doses. Following the first dose, the mean peak level was 12.5 mg/litre, mean time to peak was 8.1 hours and mean apparent elimination half-life was 6.6 hours. Pharmacokinetic data were similar following the third dose. In nocturnal asthma, Uniphyllin should be given at about 20.00 hours to coincide peak levels with the time of maximum airflow obstruction.

New method for bioavailability assessment of slow-release preparations of theophylline.

Variability in an individual's clearance of theophylline is an important consideration when estimating bioavailability. A method is described for compensating for this problem, using the serum concentration of theophylline and urinary excretion data on its major metabolites to make an estimation of the clearance after oral administration using the intravenous dose as reference. The method is particularly useful for assessing the bioavailability of slow-release theophylline preparations.

Bronchodilator therapy in obstructive lung disease.

In recent years the management of patients with obstructive lung disease has been greatly simplified by the introduction of highly selective long-acting beta adrenergic agonists, slow release theophylline preparations and locally active anticholinergic agents. The beta adrenergic compounds are the most potent and many feel that they should be the first line therapy for acute episodes of airway obstruction. Methylxanthines continue to be used effectively in chronic disease and the improved bloodlevel time profiles of theophylline that are now available from sustained-release formulations provide better control of symptoms with fewer side effects than was previously possible. The new anticholinergic compounds currently undergoing testing show great promise in selected clinical situations.

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 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.

Erratic Absorption of a Slow-Release Theophylline Sprinkle Product

The bioavailability and absorption pattern of theophylline from a slow-release theophylline sprinkle preparation were investigated in 12 asthmatic children both in fasting conditions and after a standardized meal. Theophylline given intravenously was used as a reference. Theophylline from the slow-release theophylline product was well absorbed under fasting conditions, but both absorption pattern and bioavailability were severely affected by concomitant food intake: a delay in absorption was found and the bioavailability was reduced from 91% (fasting) to 44% (P less than .001). The erratic absorption of theophylline after food intake complicates safe therapy with the preparation and calls attention to the fact that it is not sufficient to investigate the absorption characteristics of slow-release theophylline preparations under fasting conditions only.

Slow Release Theophylline Preparations are Widely Used

Slow Release Theophylline Preparations are Widely Used

THEOPHYLLINE PRESCRIBING, SERUM CONCENTRATIONS, AND TOXICITY

Slow-release theophylline preparations have been prescribed increasingly at the Brompton Hospital, and a serum theophylline assay is requested about once for every ten prescriptions. In a period of eighteen months 1913 such assays were performed, and their influence on management was assessed by retrospective analysis in two groups—113 outpatients on stable dosage with no recent exacerbations of disease; and 28 inpatients and outpatients with concentrations exceeding 25 mg/l. In those with stable treatment, there was only a loose relation between dose and serum theophylline level. High serum levels were associated with abnormal liver function, diuretic use, and duplicate prescribing. When serum theophylline levels were reported high, dosage was always reduced, whereas a low serum theophylline prompted dosage increase in only one-third of patients. Of the patients with very high serum theophylline concentrations (over 25 mg/l), 18 had been receiving oral theophylline and 10 aminophylline by infusion. 3 had seizures, of whom 2 died, and 1 patient was resuscitated after cardiac arrest. Unsuspected theophylline toxicity may be responsible for considerable hidden morbidity.

Relationship between serum theophylline levels and pulmonary function before and after inhaled beta-agonist in "stable" asthmatics.

In 9 "stable" adult asthmatics, the relationship between serum theophylline level and pulmonary function, as well as the interaction of aminophylline and inhaled beta2-agonist on pulmonary function, were studied. At varying levels of serum theophylline between 6 and 25 micrograms/ml, which were brought about by increasing oral doses of a slow-release theophylline preparation, the forced vital capacity (FVC), forced expiratory volume in one second (FEV1), airway resistance (Raw), and lung volume were assessed before and after inhalation of a B2-sympathicomimetic (isoetharine). In those subjects in whom it was possible to obtain blood levels within all 3 ranges of less than 10, 11 to 15, and greater than 15 micrograms/ml, there was a significant (p less than 0.05) increase in FEV1 between a mean level of 6.4 +/- 0.9 micrograms/ml and one of 12.8 +/- 0.2 micrograms/ml, but there was no further significant improvement at a mean value of 19.2 micrograms/ml +/- micrograms/ml. Specific airways conductance (SGaw) showed no change at increasing serum theophylline levels. In addition, inhaled beta-agonist increased FEV1 and SGaw maximally at all times, irrespective of the serum theophylline level, and there was no relationship between the response to inhaled bronchodilator and the serum theophylline level. The data indicate that unlike the patient in serious difficulty, ventilatory function was not improved by maximizing serum theophylline levels in this population of stable asthmatics. This suggests that theophylline may be less useful for the stable asthmatic patient than for the acutely ill patient.

Sustained serum theophylline concentrations during chronic twice daily administration of a slow release preparation.

Theophylline concentrations were measured in a clinical setting in 15 patients given a slow release theophylline preparation (Theo-Dur) every 12 h for reversible obstructive airways disease. Doses of 300-600 mg (464 +/- 134), 12 hourly, resulted in mean serum concentrations which increased from 11.2 +/- 2.9 micrograms/ml at 0 h to a peak of 15.5 +/- 4.6 micrograms/ml at 6 h and decreased again to 10.4 +/- 2.9 micrograms/ml at 12 h. The mean percentage fluctuation of serum concentrations (maximum minus minimum expressed as a % of the maximum) was 38.6 +/- 10.1%, range 20.3% to 54.9%. There was a significant positive correlation between % fluctuation and theophylline steady-state clearance determinations. Excluding a single heavy smoker, theophylline clearance also showed a significant inverse relationship with age. These data suggest that when this slow release preparation is given 12 hourly, satisfactorily sustained serum theophylline concentrations will be achieved in most adults.

Delay in the absorption rate of theophylline from a sustained release theophylline preparation caused by food.

British Journal of Clinical PharmacologyVolume 12, Issue 6 p. 904-905 Free Access Delay in the absorption rate of theophylline from a sustained release theophylline preparation caused by food. S Pedersen, S PedersenSearch for more papers by this author S Pedersen, S PedersenSearch for more papers by this author First published: December 1981 https://doi.org/10.1111/j.1365-2125.1981.tb01329.xCitations: 40AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References KAMPA, I.S., DUNIKOSKI, L.K., JARZABEK, J.I. & GRUBESICH, D. (1979). Comparison of three assay procedures for theophylline determination. Ther. Drug Monitoring., 1, 249– 256. RUSSELL, C.J., ELWOOD, R.K., KINNEY, D. & McDEVITT, D.G. (1980). Plasma theophylline concentrations following the oral administration of microcrystalline theophylline and a new sustained-release theophylline preparation to normal subjects. Eur. J. clin. Pharmac., 18, 351– 354. SVEDMYR, N., MELLSTRAND, T. & SVEDMYR, K. (1979). Clinical trial of a new slow-release theophylline preparation (‘Nuelin SR’). Curr. med. Res. Opin., 6, 40– 44. WELLING, P.G., LYONS, L.L., CRAIG, W.A. & TROCHTA, G.A. (1975). Influence of diet and fluid on bioavailability of theophylline. Clin. Pharmac. Ther., 17, 475– 480. Citing Literature Volume12, Issue6December 1981Pages 904-905 ReferencesRelatedInformation

Pharmaceutical Tests and Plasma Theophylline Level of Slow-Release Preparation

Plasma theophylline concentration of a slow-release theophylline preparation (SRT: Theona P) was measured by high-pressure liquid chromatography. SRT was administered to 6 healthy adults orally in dose of 100mg. Dissolution test of SRT by the rotating basket method made in accordance with U. S. P. XVIII revealed that the drug tended to dissolve slowly, dissolution rate being about 50% 6 hours after initiation of the experiment. The experiment also demonstrated that plasma concentration of theophylline reached peak about 5 hours after oral administration of SRT on the average, and about 2 hours after use of Aminophylline Tablet (immediate-release preparation).Average maximal plasma theophylline level was 1.32μg/ml for SRT as compared with 1.92μg/ml for Aminophylline. In clinical trial, the plasma concentration of theophylline was not maintained at 10μg/ml after oral administration of SRT and Aminophylline Tablet in dose of 100mg 4 times a day, respectively. The 10-μg/ml level was maintained when SRT single dose was increased to 200mg.