Is a uniform round-the-clock theophylline blood level necessary for optimal asthma therapy in the adolescent patient?

Twenty-one patients, 12 to 18 years of age, with nocturnal asthma controlled with sustained-release theophylline administered twice daily, were enrolled in a 10-week, double-blind, two-way crossover study that compared Theo-Dur tablets administered twice daily with an equivalent daily dose of Uniphyl tablets administered once daily at bedtime. Seventeen patients completed the study. The mean morning theophylline serum level obtained with Uniphyl tablets was significantly higher than that obtained with Theo-Dur tablets (13.1 versus 9.6 micrograms/ml, p = 0.02). The mean evening serum level was significantly lower with Uniphyl tablets (6.3 versus 10.1 micrograms/ml, p = 0.003). Despite these differences in serum concentrations, morning and evening pulmonary function test values (forced expiratory volume in one second and peak expiratory flow rate) and symptom scores were nearly identical for the two preparations, as was the supplemental use of aerosol bronchodilators. Once-daily dosing with Uniphyl tablets may benefit adolescent patients with nocturnal asthma by increasing compliance and providing better asthma control. In addition, the lower daytime theophylline levels produced by this preparation may also reduce long-term adverse effects on behavior and cognition.

Double-blind evaluation of methylprednisolone versus placebo for acute asthma episodes.

Twenty-eight children with persistent bronchospasm after outpatient therapy were treated for eight days with methylprednisolone or placebo in a prerandomized double-blind manner, in addition to treatment with optimal oral bronchodilators. At follow-up visits 1, 7, and 14 days after onset of therapy, a history was taken and physical examination and pulmonary function tests were performed. Initially and on the 14th day, patients underwent cosyntropin tests of adrenal function. Patients kept daily peak flow charts. Both groups improved with time. However, by 24 hours after starting methylprednisolone therapy, the placebo group continued to show reversibility after isoproterenol inhalation whereas the methylprednisolone group did not. By day 7 there were significantly more patients with normal 1-second forced expiratory volume (FEV1) and forced expiratory flow in the middle half of the forced vital capacity (FEF25-75%) in the methylprednisolone group and mean FEF25-75% was significantly higher for this group (P less than .02). By day 14, six days after finishing treatment with the study drugs, more patients in the placebo group had residual wheezing, but pulmonary function tests were now similar for the two groups. Although both groups showed a decline in cosyntropin responsiveness on day 14 compared with day 1, there was no difference between the steroid- and placebo-treated patients. This study proves that short-term corticosteroid therapy will accelerate resolution of moderately severe and severe-acute attacks of asthma without significant suppression of adrenal function.

Immunologic defects in patients with refractory sinusitis.

Sixty-one patients with chronic sinusitis who were referred for an allergy evaluation were evaluated for immunologic competence including assessment of quantitative serum immunoglobulin levels, IgG subclass levels, and response to pneumococcal and Haemophilus influenzae vaccines. In addition to chronic sinus disease, recurrent otitis media and asthma exacerbation were common problems in this group. Five patients had an elevated age-adjusted IgE level and 22 patients had positive prick tests to one or more environmental inhalants; these findings suggest an allergic component in this subgroup. Twelve additional patients had highly reactive intradermal tests to common environmental allergens, which also may be clinically significant for underlying atopy. Eleven patients had low immunoglobulin levels, 6 had low immunoglobulin levels and vaccine hyporesponsiveness, and 17 had poor vaccine response only. Thus, 34 of 61 patients with refractory sinusitis had abnormal results on immune studies, with depressed IgG3 levels and poor response to pneumococcal antigen 7 being most common. In addition to allergy, immunologic incompetence may be an important etiologic factor in patients with chronic, refractory sinusitis.

A double-blind study comparing the effectiveness of cromolyn sodium and sustained-release theophylline in childhood asthma.

The effectiveness of cromolyn sodium and theophylline on asthma in children was compared during a 3-month trial. Forty-six children (aged 5 to 15 years) with asthma were assigned at random to cromolyn or theophylline (Theo-Dur) treatment groups. Each subject received theophylline placebo or cromolyn placebo in addition to the active drugs. A methacholine challenge test was done at the start of the study to document asthma and was repeated during the third month. The theophylline dosage was regulated to obtain serum levels of 10 to 15 micrograms/mL by a physician not involved directly with patient care. Forty patients completed the study. Both theophylline and cromolyn treatment groups showed improvement from base-line status in terms of symptom scores, pulmonary function, and decreased use of inhaled albuterol. Patients treated with theophylline had more side effects and required more frequent office visits than those treated with cromolyn. Both groups had decreased sensitivity to methacholine, and for one statistical test patients treated with cromolyn improved significantly. These results indicate that cromolyn is as effective as theophylline in treating mild to moderate asthma in children; additional benefits were fewer side effects and a possible decrease in bronchial hyperactivity.

Facial characteristics of children who breathe through the mouth.

There are many claims that abnormal breathing patterns alter facial growth; however, there are limited controlled data to confirm these claims. Thirty children with allergy, aged 6 to 12 years, who had moderate-to-severe nasal mucosal edema on physical examination and who appeared to breathe predominantly through the mouth and 15 children without allergy who had normal findings from nasal examination and who appeared to breathe predominantly through the nose were evaluated. All subjects received an intraoral clinical examination and cephalometric radiograph analysis. In comparison with children who breathed through the nose, children who breathed through the mouth had longer faces with narrower maxillae and retruded jaws. This supports the hypothesis that children with nasal obstruction and who appear to breathe through the mouth have distinctive facial characteristics.

Effectiveness of terbutaline and theophylline alone and in combination in exercise-induced bronchospasm.

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.

Altered theophylline clearance during an influenza B outbreak.

During the 1980 influenza B outbreak in King County, Washington, 11 children whose asthma had previously been controlled with a stable theophylline dose, developed theophylline toxicity on this same dose. Two had seizures, eight had nausea and vomiting, and three had headaches. All had clinical evidence of a febrile viral illness. The toxicity appeared to be related to decreased theophylline clearance, which gradually returned to preillness levels over a period of one to three months. Six of ten children had serologic evidence of influenza B, which is presumed to be the cause of the altered clearance. In children receiving chronic theophylline therapy, symptoms of vomiting, headaches, or seizures during a viral illness may be due to theophylline toxicity rather than the virus. Such patients should have an immediate serum theophylline determination, even if previous levels have been in the therapeutic range.

Individualization of theophylline dosage using a single serum sample following a test dose.

Because formulas for theophylline requirement based on weight alone carry the risk of overdosing and toxicity, this study was designed to test a clearance nomogram for determining daily theophylline requirement after a known initial dose of theophylline. Twenty asthmatic children who had not taken theophylline for at least 36 hours fasted and were given one dose of anhydrous theophylline (5 mg/kg). Six hours later the serum level was measured and the appropriate dosage of sustained-release theophylline to achieve a serum level of 10 micrograms/ml was selected from the clearance nomogram. Three to seven days later a six-hour theophylline level was obtained. Of 20 patients, therapeutic levels of 10 to 30 micrograms/ml were achieved in 15, and the remaining five patients had levels close to this (range 6.2 to 16.0 micrograms/ml). The dosage requirement per 24 hours ranged from 10 to 32 mg/kg/24 hr. This method of determining theophylline requirements for children required measurement of the serum theophylline level only once for the determination of a safe and effective daily dose. It is especially valuable when follow-up is difficult and is a safe way to avoid serious overdosing while being certain of effective dosing.

Short-term double-blind evaluation of flunisolide aerosol for steroid-dependent asthmatic children and adolescents.

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.

Dyphylline versus theophylline: a double-blind comparative evaluation.

This study was a randomized double-blind evaluation of three doses of dyphylline, theophylline, and placebo for blocking exercise-induced bronchospasm (EIB). Twenty patients aged 12 to 17 years took one of the following on five separate days prior to an exercise challenge: 10, 15, or 20 mg/kg dyphylline; 6 mg/kg anhydrous theophylline; or placebo. Linear relationships were found between the log of dyphylline doses and per cent changes from baseline for PEFR, FEV1 and FEF25-75%. The 15 and 20 mg/kg doses differed significantly from placebo in preventing declines in PEFR, FEV1, and FEF25-75%. While significant, these changes were one half to one third those found with 6 mg/kg theophylline. Tremor was twice as common with theophylline. While dyphylline has therapeutic effectiveness compared to placebo for blocking EIB, its benefit is small. Further evaluations are needed to elucidate optimal dosaging for maximal effectiveness.

Cromolyn and nedocromil therapy of asthmatic children.

Controlled studies of cromolyn treatment of asthmatic children have revealed benefits beyond the incredible safety of the drug. It is now recognized that the patient with asthma will have decreased asthma and less bronchial hyperreactivity when treated for more than two months with cromolyn. Also, the reduced sensitivity of beta-receptors with chronic use of beta adrenergic drugs is abated with concomitant cromolyn use. It is hoped that the studies with nedocromil will reveal additional benefits with this class of antiasthmatic medication.

Conductive hearing loss and speech development.

The central issue about conductive hearing loss and speech development is the impact of mild to moderate hearing loss that may be intermittent. Although opinions vary considerably about what this does to the ability of the child to learn, most studies support a position of concern. This concern should focus on identification and treatment of such children, with special teaching techniques in addition to medical and surgical treatment.

The role of allergy in sinusitis in children.

Allergic rhinitis and sinusitis are independently common disorders. Studies document the presence of both disorders in the same patient 25% to 70% of the time. Because this is above the prevalence of allergic rhinitis in the general population, the literature supports that allergy is an important associated factor in sinusitis. Younger children appear to be even more at risk of sinusitis, perhaps because of small anatomic structures, more frequent viral infections, and more exposure to indoor allergens and irritants. Immunodeficiency appears to play an independent role in resistant, severe sinusitis.

Other pharmacologic agents that may affect bronchial hyperreactivity.

Although most asthmatic athletes can be adequately controlled by beta-adrenergic agents, sodium cromolyn, and/or theophylline, a few do not tolerate these medications or have suboptimal results. Cromolyn-like antiallergic drugs, newer antihistamine, antiserotonin, and antileukotriene agents as well as calcium channel blockers, antimuscarinics , alpha-adrenergic blockers, and new steroid preparations may be suitable for these individuals. Although efficacy has been demonstrated for a number of these new agents, much work remains to be done to evaluate thoroughly their potential pharmacologic effectiveness in exercise-induced asthma.