Serum Concentrations of Theophylline in Children Treated with Two Daily Doses of a Sustained-Release Theophylline Preparation

Over a 3-month period 22 asthmatic children were treated with a sustained-release theophylline preparation (Nuelin Retard®, Riker) in twice-daily doses. During the first 2 weeks of treatment slight side-effects were observed in 14 children. Over the remaining 10-week period only four children experienced minor side-effects.
Serum theophylline levels 4 hours after tablet administration were measured three times and serum levels just before tablet administration were measured once during the observation period. The average difference between the serum levels of theophylline just before tablet administration and the corresponding serum value 4 hours afterwards was 4.2 μg/ml. The serum values 4 hours after tablet administration showed an insignificant fall throughout the period and patient compliance was assessed as good.
When the average requirements of theophylline in mg/kg found by Wyatt et al. (15) (Table 2) were used as initial doses, few dosage adjustments were necessary and no serum values were greater than 26.2 μg/ml, but in order to avoid serum levels above 20 μg/ml initial doses should be decreased about 10% and final adjustment made with the aid of serum theophylline measurement under steady state conditions.
In children, Nuelin Retard given in two daily doses is capable of maintaining a constant therapeutic serum concentration for the whole 24-hour period.     

Food and Fasting Absorption of a Single Dose of a Sustained Release Theophylline Sprinkle Formulation in Children

The bioavailability and absorption pattern of theophylline from a single dose of a slow release theophylline sprinkle product (Somophyllin) were investigated in 10 asthmatic children both in fasting conditions and after a standardized breakfast. Theophylline given intravenously was used as a reference. The fasting absorption of Somophyllin was rather fast with peak serum theophylline levels 3-5 h (mean 3.7 h) after dosing. Food produced a small but statistically significant reduction in the rate of absorption of theophylline, so that the mean time to peak serum theophylline level was 5.6 h (range 4-8 h) after food. In no case was there any important difference between the absorption profiles on the test days, and the bioavailability was complete after both fasted and fed intake of the product (92.5% and 105%, respectively). It is suggested that to obtain the optimum absorption profile children should take Somophyllin with food rather than between meals.     

Lack of adverse cardiac effects of combined treatment with theophylline and albuterol in asthmatic children

Our study was designed to assess potential cardiovascular adverse effects in clinically stable asthmatic children due either to oral sustained-release theophylline or theophylline in combination with an inhaled beta-2 adrenergic agonist. Twenty-five asthmatic children were evaluated while receiving no drugs, theophylline alone, and theophylline with an inhaled beta-2 adrenergic agonist. In each phase all patients underwent 24- to 48-hour Holter monitoring and a maximal treadmill exercise test. The results show that neither theophylline alone nor combined therapy was associated with any relevant cardiovascular adverse effect, including ectopic cardiac activity. A nonsignificant increase in mean heart rate was observed between each period of study. The data suggest that the use of theophylline either alone or in combination with a beta-2 adrenergic agonist in clinically stable asthmatic children is not associated with any serious cardiovascular effect.     

The effect of metaproterenol in chronic asthmatic children receiving therapeutic doses of theophylline.

The effect of metaproterenol added to therapeutic doses of theophylline was compared with a combination of placebo and theophylline by measurement of the forced expiratory volume in 1 sec (FEV₁), forced vital capacity (FVC), and maximum midexpiratory flow rate (MMEFR) in 17 asthmatic children in a double-blind crossover study. Plasma theophylline levels were measured at 1.5 hr (peak) and 6 hr (trough) after drug administration on all test days. Children weighing less than 60 pounds received 10 mg of metaproterenol (1 tsp), while those weighing more than 60 pounds received 20 mg every 6 hr. The mean peak theophylline level for both metaproterenol and placebo treatment days was approximately 10 μg/ml, while the trough was 6 μg/ml. Metaproterenol caused a significantly greater increase in FEVI (p < 0.05) of 17% at 1.5 hr when given with theophylline than the placebo- theophylline combination. The metaproterenol effect on MMEFR was even greater with increases over placebo of more than 80% at 1.5 hr and 2 hr (p < 0.0025) and 30% at 3 hr and 4 hr (p < 0.05). No increase in adverse effects with the metaproterenol-theophylline combination compared with placebo-theophylline was observed. This study suggests that metaproterenol can improve pulmonary function of both large and small airways when added to moderate theophylline doses without risking increased side effects in asthmatic children.     

Asthma patients requiring unusually high doses of theophylline

We often see severe asthma attacks occur in patients taking high doses of theophylline and disappear soon after intravenous injection of aminophylline. Theophylline concentration in the serum was investigated in those cases. Twenty five asthmatic patients, 14 males and 11 females, 16-17 years of age, visited our out-patient clinic 41 times in total over a period of 9 months suffering from dyspneic attacks of such severity that they had difficulty in speaking and walking although they had taken at least 200 mg theophylline within 6 hours and 400 mg within 12 hours. All cases were treated with iv infusion of 2.8-14 ml of 2.5% aminophylline for 5-15 minutes until the dyspneic symptoms disappeared. Theophylline levels in the serum (micrograms/ml) before the treatment were 2.0 in 1 case, 6.0-9.8 in 8, 10-20 in 23, and over 20 in 9 cases. Levels after the treatment were 5.8 in 1 case, 10-20 in 15, and over 20 in 25 cases. In one patient, a 27-year-old female, 300-400 mg of theophylline, aminophylline, or choline theophyllinate tablets could increase theophylline concentration in the serum only 4.8 micrograms/ml or less, while her theophylline clearance was normal. The present study revealed that there are asthmatic patients requiring unusually high doses of theophylline, partly because some of them have problems in absorption of theophylline, and partly because many of them need higher levels of blood theophylline than those usually thought of as standard therapeutic concentrations.     

Effect of theophylline on improvement of the pulmonary function in the treatment of acute episodes of asthma: the influence of the severity of acute asthma

The bronchodilating effect of theophylline was studied from the perspective of its influence on the severity of acute asthmatic attack and where its acting site is located on bronchi. Pulmonary function including maximal expiratory flow-volume curve breathing of room air and of a gas mixture containing 80% helium and 20% oxygen (He-O2) was measured at each incremental plasma theophylline concentration plateau (5, 10, and 15 micrograms/mL) in 12 acutely ill asthmatic patients. Before starting the administration of theophylline, clinical findings were used to classify the severity of the asthmatic attack into mild, moderate, or severe groups. Our data suggested that theophylline acts on both the central and peripheral airways and that theophylline improves the airway obstruction in a dose-dependent fashion when the severity of acute attack is mild.     

Use of a twelve-hour theophylline preparation in chronic adult asthmatics

Twenty-one adult chronic asthmatic patients were studied while taking a 12-hour sustained-action theophylline tablet. Pulmonary function testing and serum theophylline levels were monitored for 12 weeks, including testing every two hours over one dosing interval on the final day of the study. Results indicate the preparation tested produced sustained stable theophylline levels for a full 12 hours, with pulmonary function also remaining elevated and stable during this period. There was minimal toxicity reported over the 12-week period and no evidence of tolerance.     

Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol

The effects of theophylline on allergen-induced airway obstruction and bronchial hyperresponsiveness were investigated in allergic rabbits. This allergic rabbit model was developed in our laboratory and stimulates the human model of allergic asthma in several aspects. Four allergic rabbits with hyperreactive airways were challenged with ragweed to elicit early- and late-phase asthmatic responses and subsequent increased airway responsiveness. Two to three weeks later, the rabbits received theophylline (5 mg/ml, nebulized for 3 min) prior to a second allergen challenge. Theophylline significantly inhibited the allergen-induced early- and late-phase asthmatic responses by 38% (P<0.05) and 49% (P<0.05), respectively. Further theophylline inhibited the allergen-induced increase in lung resistance by 42% (P<0.05) during the late-phase responses. Theophylline also inhibited the allergen-induced bronchial hyperresponsiveness by 39% (P<0.05) at 24h. These data suggest a potential anti-inflammatory effect of theophylline in preventing allergen-induced asthmatic responses and bronchial hyperresponsiveness.     

Perforated gastric ulcer in an asthmatic treated with theophylline and steroids. Case report and literature review

We presented a patient with status asthmaticus treated with a combination of theophylline and prednisone who developed a perforated gastric ulcer. The relative etiologic significance of the stress of status asthmaticus, administration of theophylline, or corticosteroids is open to question. The literature, except for anecdotal reports, does not support a significant increase of ulcers in asthmatic patients on either theophylline or steroids. A study following large patient groups on theophylline and a combination of theophylline and steroids might clarify the risk of ulcer formation in patients being treated with these medications for asthma.     

Studies of free theophylline in asthmatic patients

Total and free theophylline concentrations were examined by fluorescent immunoassay using serum from 48 asthmatic patients treated with sustained-release theophylline formulation. Total and free theophylline concentrations showed a good correlation. The mean % free theophylline (free theophylline concentration X 100/total theophylline concentration) was 44.7% in children and 43.6% in adults. The % free theophylline had no relation to age of the patients or total theophylline concentration. However, the % free theophylline increased correlatively when serum pH or albumin was decreased. As changes in free theophylline concentration influence therapeutic responses and side effects, an assessment of serum pH and albumin in patients treated with theophylline is necessary.     

Sustained release theophylline for the forgetful asthmatic

Several theophylline pharmacologic strategies were tested for the forgetful medication-dependent asthmatic who frequently initiates treatment from below the therapeutic range of 10 to 20 micrograms/mL. Theodur was found to give comparable if not higher levels (two, eight, and 24 hours) starting from 0 microgram/mL than Slophyllin Gyrocap during a multiple dose 28-hour study. In a single dose 12-hour study, Theodur 100-mg tablets gave higher levels during the first nine hours than Theodur 200-mg tablets. Theodur 100-mg tablets may be preferred for the forgetful asthmatic who can sustain pulmonary function despite greater fluctuation with theophylline levels.     

Theophylline increases serum uric acid levels

The present study was undertaken to investigate the effect of theophylline on serum uric acid and then to elucidate the mechanisms of action of theophylline as a cause of hyperuricemia. There was a significant increase of serum uric acid levels in male asthmatic patients who received theophylline compared to male control subjects without theophylline (6.3 +/- 0.4 mg/ml, mean +/- SEM, versus 4.3 +/- 0.2 mg/ml, p less than 0.01). A significant correlation of serum levels of uric acid and theophylline was demonstrated in asthmatic patients who received 200 to 400 mg sustained-release theophylline (male group, r = 0.480, p less than 0.001; female group, r = 0.398, p less than 0.01). Intravenous administration of aminophylline in three healthy adult male patients did not inhibit uric acid clearance, suggesting that inhibition of excretion of uric acid by theophylline is unlikely. Theophylline slightly inhibited hypoxanthine guanine phosphoribosyltransferase activity in human erythrocyte lysates at concentrations over 5 mM that is considerably more than therapeutic concentrations of theophylline as determined by the conversion of [14C]hypoxanthine to [14C]inosinic acid. Theophylline caused a moderate inhibition of [14C]hypoxanthine uptake by K-562 cells (approximately 50%) at 10mM that is over 100 times as high as those achieved clinically. Further studies remain to be performed to elucidate the exact mechanisms of theophylline-induced hyperuricemia.     

Erythrocyte glutathione peroxidase activity in asthmatic children

Erythrocyte glutathione peroxidase (GPX) levels were determined in 56 asthmatic children. Lowest levels were found during acute asthmatic attack (13.53 +/- 2.94 IU) which were significantly less than controls (20.4 +/- 5.44 IU) (P less than .001). Post-attack levels 1 week later rose significantly (16.77 +/- 2.63 IU), but were still less than normal values (P = .001). GPX levels (16.96 +/- 3.28 IU) were less than controls (P less than .03) even in patients with mild symptomatology. Asymptomatic patients receiving theophylline had normal levels. Low GPX activity in asthmatic patients may play a role in the pathogenesis of the disease.     

Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine

Allergen-induced increase in airway hyperresponsiveness can be used as a model of airway inflammation for assessing antiasthma pharmacologic agents. Steroids and cromolyn, but not beta-agonists, inhibit this increase; theophylline, recently suggested as having anti-inflammatory effects, has not been evaluated in this model. Six atopic subjects with asthma and with late asthmatic responses (N = 5) and postallergen reduction in a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) (N = 6) were studied. Sustained-release theophylline (Theo-Dur; Astra Pharmaceuticals Canada, Ltd., Mississauga, Canada), 300 mg, and placebo were administered single-blind twice daily for eight doses up to 1 hour before allergen inhalation; cromolyn sodium, 10 mg, was administered in a single dose 10 minutes before allergen inhalation on another day as a "positive control." Mean theophylline levels were in the low therapeutic range, 57 +/- 17 and 58 +/- 13 mumol/L 1 and 8 hours after the last tablet. The FEV1 was 7% and 9% greater after the seventh and eighth doses of theophylline versus placebo (p less than 0.05). Theophylline also produced a significant (p less than 0.05) twofold increase in methacholine PC20. There was a 40% (p = 0.06) reduction in early asthmatic fall in FEV1 and a 25% (not significant) reduction in late FEV1 fall when theophylline was compared to placebo. Theophylline did not influence the geometric mean allergen-induced fall in methacholine PC20 delta log PC20; this was true individually in five of the six subjects. By contrast, cromolyn sodium inhibited all aspects of the allergen response completely.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of serum theophylline concentrations following administration of sustained-release beads in applesauce to asthmatic preschool children

A sustained-release theophylline preparation (Theo-Dur Sprinkle) was evaluated in young asthmatic patients aged 1 to 6 years and receiving a daily dose of 23.4 +/- 2.0 mg/kg (mean +/- SD) to determine, on the basis of serial serum concentrations obtained over a 12-hour dosing interval at steady state, the suitability of such a product in patients likely to metabolize the drug very rapidly. Peak theophylline concentrations of 15.1 +/- 4.1 mg/L were achieved 5.5 +/- 1.5 hours after dosing. The mean maximum to minimum concentration difference was 6.9 +/- 2.2 mg/L for the dosing interval studied. Fluctuations in theophylline concentration less than 100% were achieved in nine of the 12 study patients. Use of the "sprinkle-technique" with Theo-Dur Sprinkle appears to be a simple and effective method of maintaining acceptable fluctuations in serum theophylline concentrations in preschool asthmatic children.     

Induction of suppressor T cells in asthmatic children by theophylline treatment

The absolute T-cell numbers and function, and the T-suppressor-cell subset were tested in eleven children with extrinsic asthma prior to and 1 month after theophylline treatment. Low mean T-suppressor-cell number and function was found in the asthmatic children, which returned to normal levels and function after 1 month of theophylline treatment. A normal mean T-cell number was found in this group of children prior to, and 1 month after, theophylline treatment. An obvious correlation between the clinical severity of the asthma and the number of T suppressor cells was found. It is suggested that theophylline most probably activated the T suppressor cells in the asthmatic children.     

A comparative trial of the clinical efficacy and pharmacokinetics of 12-hour and 24-hour controlled release theophylline preparations in patients with chronic asthma

A double-blind crossover comparison of a 12-hour theophylline preparation (Theo-Dur) and a 24-hour theophylline preparation (Theo-24) was conducted with 20 young adult chronic asthmatic patients requiring daily bronchodilator therapy. The study group included 11 males and nine females ranging in age from 12 to 28 years. Clinical status and serum theophylline levels were monitored during the 4-week dosing interval on each medication. On the last day of each test period subjects were monitored closely throughout a 24-hour period. The results indicated little clinical difference between the two medications although there were statistically significant differences in the pharmacokinetic behavior between the two theophylline preparations.     

Effect of in vitro colchicine and oral theophylline on suppressor cell function of asthmatic patients.

Extrinsic asthmatic patients have been reported to have a deficiency of concanavalin A (Con A)-induced suppressor cell function. We tested whether in vitro colchicine and oral theophylline can correct this immunoregulatory abnormality. Asthmatic patients' mononuclear cells were incubated with Con A and/or colchicine and then suppression of proliferation was measured by coculture of these cells with healthy volunteers' mononuclear cells and phytohaemagglutinin. The Con A induced suppressor cell function of 29 theophylline treated patients (26 +/- 16%, mean +/- s.d.) was significantly (P less than 0.002) increased as compared to 21 untreated patients (12 +/- 10%) but significantly (P less than 0.01) decreased as compared to 45 healthy volunteers (39 +/- 17%). A pharmacological concentration (10(-8) M) of colchicine had no significant effect on Con A-induced suppressor cell function of 19 untreated patients (from 12 +/- 9% to 9 +/- 22%) but significantly (P less than 0.05) increased Con A-induced suppressor cell function of 20 theophylline treated patients (from 26 +/- 17% to 36 +/- 19%). Thus asthmatic patients have decreased Con A-induced suppressor cell function which is partially corrected by oral theophylline and almost completely corrected by oral theophylline plus in vitro colchicine. This synergistic effect raises the possibility that oral colchicine together with theophylline may be useful in treating patients with extrinsic asthma.     

Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects

To determine whether oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by allergens, we examined six asthmatic subjects who developed a dual asthmatic reactions after allergen bronchoprovocation with Dermatophagoides pteronyssinus or with grass pollen. We gave oral slow-release theophylline and placebo to each subject for seven days in two series of experiments in a double-blind, randomized, crossover study. The individual daily dose of theophylline (4.7 to 16.6 mg/kg/day, divided into two doses) was calculated for each subject by measuring individual theophylline clearance and optimal daily dosage. During treatment with placebo, the subjects developed dual asthmatic reactions, ie, FEV1 decreased from 4.1 +/- 0.17 L before bronchoprovocation to 3.2 +/- 0.14 L at 15 minutes and to 3.2 +/- 0.19 L at seven hours after allergen bronchoprovocation. By contrast, during active treatment FEV1 decreased from 4.2 +/- 0.28 L to 3.9 +/- 0.26 L at 15 minutes, and to 3.8 +/- 0.13 L at seven hours (both cases, P less than .03 compared with placebo). Mean serum theophylline concentration was 13.2 +/- 0.6 mg/L. Although 1 week's treatment with slow-release theophylline did not modify significantly either prechallenge airway responsiveness to methacholine or its increase after allergen inhalation challenge, in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine induced by allergens compared to placebo and control day (P less than .05). These results suggest that slow-release theophylline may inhibit allergen-induced asthmatic reactions and the associated increase of airway responsiveness, suggesting some antiinflammatory effects for this drug.     

A comparison of a theophylline-ephedrine combination with terbutaline.

In a single-blind, crossover study 10 adult asthmatic patients received a theophylline-ephedrine combination tablet (theophylline 90 mg, ephedrine 16 mg and phenobarbital 25 mg in an immediate release layer and theophylline 90 mg and ephedrine 32 mg in a sustained release layer) twice daily or terbutaline 5 mg three times daily for two weeks. There was no significant difference in bronchodilator response to a single dose of the study drugs on either the initial day of treatment or after two weeks of continuous therapy. Mean increases in serum cyclic-AMP levels produced by both drugs were not significantly different. Mean peak plasma theophylline levels were 2.9 +/- 1.3 microgram/ml following the initial dose and 7.3 +/- 3.4 microgram/ml after two weeks of continuous dosing with the combination drug. No adverse effects on blood pressure or pulse rate were observed to either drug. Overall, the incidence and severity of reported side effects (tremor, nausea and nervousness) were less with the theophylline-ephedrine combination.