Elliot F. Ellis

Relationship between theophylline concentration in plasma and saliva of man.

The concentration of theophylline in the plasma and saliva of 7 normal adults receiving single oral doses of 200 mg theophylline per square meter of body surface area (BSA) was determined spectrophotometrically over 8 hours. There was an excellent linear relationship between theophylline concentrations in plasma and saliva, over a plasma concentration range of 4 to 14 µg per milliliter. Theophylline concentrations in the saliva were about 48% lower than in the plasma and are similar to the concentration of free (not protein‐bound) drug in the plasma. There is very little intersubiect and intrasubiect variation of theophylline blank values in plasma and saliva, in the recovery of theophylline from plasma and saliva, and in the proportionality factor that relates saliva to plasma concentrations of the drug. These observations suggest that theophylline determination in saliva may be a convenient, painless, and noninvasive method for routine monitoring of theophylline levels.

The effect of troleandomycin on methylprednisolone elimination

Troleandomoycin (TAO), a macrolide antibiotic, has an apparent steroid-sparing effect when used in the treatment of severe steroid-dependent asthma. This study was designed to investigate the effect of TAO on methylprednisolone elimination. Pharmacokinetic studies were performed before and 1 wk after starting TAO in 10 severe steroid-dependent asthmatics. Baseline total body clearance of methylprednisolone was 406 +/- 139 (mean +/- SD) ml/min/1.73 m2 and decreased significantly (p < 0.001) to 146 +/- 57 ml/min/1.73 m2 1 wk after TAO therapy was initiated. Methylprednisolone half-life was 2.46 +/- 0.75 hr before TAO and increased significantly (p < 0.01) to 4.63 +/- 1.35 hr after 1 wk on TAO therapy. A follow-up evaluation of methylprednisolone pharmacokinetics in three patients after at least 1 mo on TAO therapy demonstrated continuation of the reduced methylprednisolone elimination. TAO inhibition of methylprednisolone clearance may contribute to the beneficial effects observed initially with combined methylprednisolone-troleandomycin therapy in severe steroid-dependent asthma.

Dose‐ and time‐related effect of troleandomycin on methylprednisolone elimination

Effects of varying doses of troleandomycin (TAO) on methylprednisolone disposition were examined in five steroid‐dependent asthmatic patients. The characteristic reduction in methylprednisolone elimination in the presence of TAO after a 40 mg IV methylprednisolone was also present after methylprednisolone doses as low as 4 mg. In patients receiving continuous TAO on an every‐other‐day basis, inhibition of methylprednisolone elimination was impaired to a greater extent on the “day on” TAO than on the “day off” TAO. Methylprednisolone elimination on the day off TAO was still slower than that before TAO, however. TAO on a multiple‐dose schedule resulted in greater reduction of methylprednisolone elimination than after a single TAO dose. These results suggest that TAO induces immediate and continued inhibition of methylprednisolone disposition.

Steroid-specific and anticonvulsant interaction aspects of troleandomycin-steroid therapy☆

Troleandomycin (TAO) is a macrolide antibiotic that has an apparent steroid-sparing effect when used in the treatment of severe steroid-dependent asthmatic patients. Recent observations demonstrated the effect of TAO on inhibiting methylprednisolone elimination, possibly contributing to its beneficial effects. Prednisolone and methylprednisolone disposition were studied before and 1 wk after initiation of TAO therapy in three patients. Methylprednisolone elimination was characteristically impaired in the presence of TAO therapy; however, there was no apparent effect on prednisolone elimination. Methylprednisolone elimination was also evaluated before and after initiation of TAO therapy in three patients receiving concomitant anticonvulsant therapy with phenobarbital-1, phenytoin-2. Methylprednisolone clearance before TAO was at least 4 times faster than normal and was probably related to enzyme induction by the anticonvulsant medication. Methylprednisolone clearance was subsequently reduced by approximately 70% in the presence of TAO therapy. The effect of TAO on corticosteroid disposition is steroid-specific and TAO can diminish the effect of certain drugs on the induction of corticosteroid metabolism.

Inhibition of exercise-induced asthma by theophylline

Although an association between exercise and provocation of asthma has been recognized for 300 yr, Jones et al., ’ pediatricians at Alder Hey Children’s Hospital in Liverpool, appear to have been the first to attempt to assess the effect of drugs as modulators of the exercise-induced bronchoconstriction phenomenon. Among the drugs they investigated was the choline salt of theophylline, a formulation that contains 64% anhydrous theophylline. In a single-dose study in which the subjects were administered anhydrous theophylline of the equivalent of between 4.5 and 5.8 mg/kg body weight several hours before exercise challenge, the postexercise fall in FEV, was completely or partially prevented in eight of nine subjects, and Jones et al. concluded that theophylline was protective against exercise-induced wheezing. In retrospect, it appears that the FEV, was measured before drug administration and not immediately before exercise and thus one does not know how much of the putative inhibition of exercise-induced asthma (EIA) was due to the bronchodilator effect of theophylline. Anderson et al.’ have emphasized the importance of measuring expiratory flow rate immediately before exercise so that the bronchodilating effect of the drug and its inhibitory effect on EIA can be considered separately. Nonetheless, in the study of Jones et al., the maximal FEV, after exercise was observed at a mean of 90 min after drug administration, which would coincide with the time of the peak serum theophylline concentration after administration of a rapidly absorbed product such as the one used. This was the first suggestion of a pharmacodynamic effect of theophylline in asthma. During the past decade there have been 10 additional studies2-” in which the efficacy of theophylline in the prevention of EIA has been investigated (Table I). While these studies are not strictly comparable because of a number of differences in experimental design and particularly in dose of theophylline, there are some generalizations that can be made. First, the results of these studies have uniformly shown that the-

MULTICENTRE EVALUATION OF DISPOSABLE VISUAL MEASURING DEVICE TO ASSAY THEOPHYLLINE FROM CAPILLARY BLOOD SAMPLE

A device using enzyme immunochromatography to indicate visually theophylline concentration in a small capillary blood sample was evaluated for precision and accuracy at four hospitals. Preliminary studies indicated sensitivity as low as 2.5 micrograms/ml, and accuracy and precision matched those in test samples ranging from 5 to 30 micrograms/ml. Absence of theophylline was also reliably detected. Paired samples of capillary and venous blood from 214 patients were used to compare this method with four standard laboratory assays. Correlations with the standard assays were 0.93-0.97, slopes 1.00-1.27, and y intercepts -1.91-0.46. The within-run coefficients of variation on twenty replicate patient sample analyses at the four hospitals were 5.1-9.7% and between-run coefficients of variation on a 15.9 microgram/ml control 5.7-9.4%. This disposable device for theophylline monitoring, which can be done within 15 min at the patients side without instruments, is sufficiently accurate to replace laboratory analysis for routine therapeutic drug monitoring.

Corticosteroid regimens in pediatric practice.

The most common pediatric adverse effects of corticosteroids are growth suppression and posterior subcapsular cataract. They develop insidiously but can be minimized by the approaches described.

Pharmacologic therapy of asthma.

Asthma is treated by avoiding the precipitants of symptoms, by a trial of hyposensitization (immunotherapy) if the precipitant cannot be avoided, and principally by pharmacologic therapy. Acute attacks have been most widely treated with epinephrine, but adrenergic aerosol bronchodilators and aminophylline are being used increasingly. When an acute attack of asthma does not respond to treatment, a diagnosis of status asthmaticus should be considered and the patient treated in a hospital intensive care unit because of the potentially life-threatening sequela of respiratory failure. Periodic mild episodes of asthma usually respond to administration of an oral bronchodilator. Chronic low-grade asthma is best treated with an around-the-clock regimen of theophylline. Patients whose asthma is not under satisfactory control with conventional bronchodilators may be given a trial of cromolyn sodium. Chronic severe cases may be treated with corticosteroids, but these drugs must be skillfully administered to avoid adverse effects.