Biomedical subjects
Publications and source records attributed to C W Bierman.
A severe generalized multisystem allergic reaction occurred in a 16-month-old infant following the use of trimethoprim-sulfamethoxazole. Acute interstitial nephritis developed three weeks following the onset of this reaction and resolved after three months. This is the first description of this renal toxicity with TMP-SMX in a child.
We have studied the reproducibility of the change in maximum expiratory flow rates after breathing helium/oxygen (He/O2) mixtures in 12 asthmatics at rest and after exercise. Each subject performed four identical exercise tests which caused a similar degree of exercise-induced bronchospasm (EIB) on each occasion. We compared flow rates at 50% of the vital capacity (V50) breathing He/O2 to those breathing air at rest, and with the lowest V50 on air after exercise. Those subjects showing an increase of greater than 20% in V50 with He/O2 compared to the corresponding air value were termed "responders". At rest the responder status after He/O2 was more consistent than during EIB. Six subjects were non-responders consistently on up to 12 separate measurements at rest while the other five subjects were non-responders on all but one occasion and the remaining subject a responder on seven of eight measurements. During EIB all but one subject showed a He/O2 response. A response was seen consistently in six subjects but the actual percentage change in V50 with helium varied greatly. One subject remained a non-responder after exercise and the other five were He/O2 responders after only two or three of the four test runs, and non-responders on the remainder. The lack of consistency of our data, particularly during EIB makes the interpretation of the He/O2 breathing test less useful than originally claimed.
The efficacy of ketotifen, a tricyclic benzocycloheptathiophene derivative, was assessed in an outpatient clinical trial and in a group of 12 asthmatic subjects with exercise-induced asthma. Subjects in the outpatient trial had mild asthma and consisted of two groups: a group of 24 atopic asthmatics with at least one positive skin test reaction and with an associated history of bronchial reactivity to at least one allergen; and a group of eight asthmatics with one or more positive skin prick tests but not bronchial reactivity to an allergen. Both groups took four weeks medication of ketotifen 1 mg bd and placebo in a randomised double-blind crossover study. There was no difference between ketotifen and placebo for any measurement made during the study and consequently no evidence of drug efficacy. The exercise study followed a standardised protocol and each subject took in random double-blind order, placebo, 1 mg, 2 mg, and 4 mg ketotifen two hours before exercise. There was no difference in the mean decreases in lung function from pre-exercise baseline values after three doses of ketotifen than with placebo. Drug levels suggested ketotifen was well absorbed. It would appear that if given for a period of only four weeks ketotifen had no beneficial effects in the management of mild asthma, and that a single dose before exercise does not modify exercise-induced asthma.
The purpose of this study was to compare the effectiveness of flunisolide aerosol prescribed as .5 mg (two inhalations) twice daily and placebo in terms of oral steroid sparing ability in a population of 32 known steroid-dependent children and adolescents. Patients were stabilized on the lowest tolerated dose of daily AM or alternate AM oral corticosteroid for at least one month before entering the study. They were randomly assigned to either flunisolide or placebo treatment for the 12-week, double-blind trial. Patients were seen every two weeks for symptom assessment, physical examination, and pulmonary function testing. Tests of adrenal function were done initially and at the study's conclusion. The flunisolide group had improved asthma control compared with the placebo group. The daily oral steroid requirement decreased in 100 percent of the flunisolide group compared with 53 percent of the placebo group (P less than .01). Pulmonary function and endocrine function remained stable for both groups. There were no adverse effects. Flunisolide aerosol in doses of .5 mg twice daily appears to be topically active and to have oral steroid potential without apparent adverse effects.
Theophylline and terbutaline, alone and in combination, were evaluated for effectiveness in treating exercise-induced bronchospasm (EIB) when used at doses that should be tolerated by adolescents taking them intermittently: theophylline, 250 mg (fast release) and terbutaline, 2.5 mg. Twenty-one subjects, 12 to 19 years of age, with EIB performed standardized exercise tests on four separate days and received either theophylline, terbutaline, the combination, or placebo in a prerandomized double-blind manner prior to exercise. Exercise tests were performed two and five hours after each study drug administration. Blood samples were drawn before and again two and five hours after drug administration for theophylline level. Pulmonary function [forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and forced expiratory flow rate (FEF 25% to 75%)] was recorded before and after exercise. All of the active treatments were better than placebo in diminishing EIB. The combination was statistically better than terbutaline or theophylline alone. The effect of theophylline was not significantly different from that of terbutaline. The combination induced significantly more tremor than either agent individually. Either drug alone or the two in combination is effective for diminishing EIB. Although the combination may have additive properties for some patients, the increased incidence of tremor may diminish its appeal. Either drug alone or in combination is effective in decreasing EIB for at least five hours, which makes them practical choices for treatment of school-aged children.
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Cloprednol is a new oral corticosteroid with a short half-life that is presently under investigation for use in asthma. Seventeen steroid-dependent children and adolescents were switched from daily treatment with prednisone to cloprednol for a one-year study. Patients showed a statistically significant improvement in symptoms while receiving cloprednol therapy. Two patients had extraordinarily good responses. Growth trends, bone age, and chest roentgenograms were not remarkably changed by cloprednol. Pulmonary function was stable. There was a significant improvement in fasting morning cortisol levels and ability to respond to metyrapone and adrenocorticotropic hormone (ACTH) challenge. Cloprednol appears to be a promising drug for steroid-dependent patients who require oral corticosteroid therapy.
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This study evaluated growth, chest radiographic manifestations, pulmonary function, and function of the pituitary-adrenal axis before and after therapy with cromolyn sodium in two groups of asthmatic youngsters, ie, 18 steroid-dependent patients and ten nonsteroid-dependent patients. The following three groups evolved: (1) steroid-dependent patients; (2) patients weaned from therapy with steroids; and (3) nonsteroid-dependent patients. Growth failure and cataracts were limited to the steroid-dependent group, while abnormalities of the lungs and pituitary-adrenal axis occurred in all three groups. Symptomatic benefits from therapy with cromolyn were striking for all groups. Chest x-ray films and the distribution of alveolar ventilation were more likely to reflect this clinical improvement than tests of pulmonary function and analyses of blood gas levels. Endocrine abnormalities in the steroid-dependent group were significant and were not quickly reversed by withdrawal of therapy with steroids. Even nonsteroid-dependent patients had abnormalities which may be related to having chronic asthma. Therapy with cromolyn seemed to promote some restoration of the function of the pituitary-adrenal axis, as indicated by better responsiveness to administration of metyrapone, which correlated with improved symptomatic control of asthma.
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Serum theophylline concentrations were measured in 17 children and adolescents with acute asthma who received an aminophylline loading dose of 7 mg/kg and a constant infusion of 15 mg/kg/24 hours. The mean total theophylline clearance rate was 1.32 +/- S.D. 0.66 ml/min/kg. Hypoxia, and in two patients, acidosis, did not appear to significantly influence theophylline clearance rates. Inter-individual differences in clearance rates were great. No child experienced symptoms or signs of theophylline toxicity during the study. If serum theophylline concentrations cannot be monitored readily, an aminophylline infusion rate of 15 mg/kg/24 hours can be used safely in patients with acute asthma, but in most patients this infusion rate will not provide serum theophylline concentrations in the desired therapeutic range of 10-20 microgram/ml. Monitoring of serum theophylline concentrations during aminophylline infusion is desirable in order to individualize infusion rates, and achieve optimal bronchodilation without toxicity.
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Efficacy and dose-response activity of oral theophylline were evaluated in 21 asthmatic children, using inhibition of exercise-induced bronchospasm (EIB) as a therapeutic marker. An aqueous theophylline suspension free of alcohol, sugar, and dye was found to be effective for prevention of EIB when given in usual maintenance doses of 4 to 6 mg/kg every 6 hours for 3 weeks, following single loading doses of 8 mg/kg. Pulmonary function measurements (FEV1, FEF25%-75%, PEFR) following standardized treadmill exercise stress were signifcantly improved during both acute and chronic theophylline administration compared to pre-drug control evaluations. There were no signs of developing tolerance to theophylline. The drug produced at least 50% inhibition of EIB in 16 to 21 patients treated. Individualized adjustment of maintenance dosage resulted in optimal theophylline serum concentrations of 10 to 18 microgram/ml in 17 patients. Signs of drug toxicity were observed only when serum levels exceeded 20 microgram/ml following loading doses in 6 patients. Although some children required higher maintenance dosage because of variability in theophylline pharmacokinetics, no child experienced adverse effects after dosage adjustment. Serum half-life ranged between 86 and 351 minutes (mean, 259 minutes); mean peak serum concentration of theophylline after 3 weeks of treatment was 14.9 microgram/ml.
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