Adverse effects of brompheniramine on pulmonary function in a subset of asthmatic children

The role of antihistamines in the therapy of bronchial asthma has remained controversial. Early studies suggested a possible aggravation of symptoms but more recent studies implied their safety. Ten asthmatic children who reported a feeling of chest tightness and subsequent wheezing after taking a preparation containing brompheniramine maleate were studied in addition to 10 control asthmatic children who reported no such adverse effect. All children were only intermittently symptomatic and did not require constant bronchodilator therapy. They were well at the time of the study. Challenges were performed with the antihistamine alone (4 mg of brompheniramine maleate), a decongestant-antihistamine combination (4 mg of brompheniramine maleate, 5 mg of phenylephrine HCl, 5 mg of phenylpropanolamine HCl), and a placebo. Results indicated a statistically significant decrease in pulmonary function in the study children when challenged with the antihistamine and decongestant-antihistamine preparation but not when challenged with the placebo. The 10 control asthmatic children did not exhibit this phenomenon and premedication with theophylline prevented the decrease in pulmonary function in the study group. Therefore a subset of asthmatic children does appear to exist in whom the use of an antihistamine may be harmful.     

Nifedipine in bronchial asthma

In 11 patients with bronchial asthma and regular overnight falls in PEFR of greater than 15%, we demonstrated significant bronchodilation restricted only to large airways after the administration of a single dose of 10 mg of nifedipine. A statistically significant increase in PEFR, SGaw, and FEV1 was noticed at 1 and especially 2 hr after nifedipine administration. During 4 days of nifedipine treatment (10 mg t.i.d.), the overnight fall in mean PEFR was statistically significant (p less than 0.02) and less than the mean fall of PEFR during the 4 days of placebo treatment. Thus nifedipine does modify the basal bronchial tone of patients with asthma and diminishes the circadian swing of airway resistance.     

The short-term bronchodilator effects of fenoterol and ipratropium in asthma

We studied the bronchodilator effects of inhaled fenoterol, a relatively selective beta-2 adrenergic agent, and ipratropium an anticholinergic drug, singly and in combination in 10 patients with asthma. The period of observation was 6 hr after aerosol administration. The six drug regimens used were fenoterol 100 micrograms, fenoterol 200 micrograms fenoterol 50 micrograms combined with 20 micrograms of ipratropium, fenoterol 100 micrograms combined with 40 micrograms of ipratropium, 40 micrograms of ipratropium, and placebo. Measurements consisted of spirometry with determination of forced expiratory volume in one second (FEV1), maximal expiratory flow at 50% of vital capacity (V50), specific airway conductance, lung volumes, and heart rate. Bronchodilation with regimens containing fenoterol was rapid, with 75% of the maximum response achieved by 5 min, while the peak effect of ipratropium was delayed for 1 to 2 hr. Fenoterol 100 micrograms produced approximately half the degree of improvement in FEV1 and V50 compared with 200 micrograms of fenoterol. The addition of 40 micrograms of ipratropium to 100 micrograms of fenoterol resulted in bronchodilation equivalent to 200 micrograms fenoterol and was associated with a more prolonged effect than fenoterol 100 micrograms. Tremor was observed in two-subjects inhaling fenoterol 200 micrograms but was not observed with any other regimen. It is concluded that the combination of inhaled ipratropium and fenoterol is an effective bronchodilator in asthma, achieving efficacy similar to that of fenoterol alone but with fewer side effects.     

Characterization of the late response in exercise-induced asthma

Nine young adult subjects who developed asthma after a standard treadmill exercise test were studied. Pulmonary function tests were performed before and after exercise and serially for at least 6 hr afterwards. The subjects performed pulmonary function tests while breathing room air and after breathing an oxygen-helium mixture with each test. Although pulmonary function returned to normal within 3 hr after exercising in all subjects, eight of the nine had late asthmatic reactions 3 to 5 hr afterward. In general the late response was less severe than the initial response. Two subjects, however, noticed clinical asthma. In the immediate response, eight of the nine subjects were helium "responders," suggesting that the immediate response involved both large and small airways. In the late response, seven of eight subjects were helium "nonresponders," suggesting that the late response occurred primarily in small airways.     

Failure of children with asthma to respond to daily aspirin therapy

Adverse reactions to aspirin in asthmatic patients have been widely described in the past. In contrast to this more frequent complication, several authors have published reports suggesting that aspirin and other nonsteroidal anti-inflammatory drugs can improve asthma. We studied the effect of long-term aspirin administration in children with moderately severe asthma. Ten children who showed no immediate effect of aspirin challenge (either adverse or beneficial) were placed in a 9 wk, double-blind crossover study, receiving aspirin (10 gr twice daily) or placebo for 4 wk, then a 1 wk washout period, followed by aspirin or placebo for 4 wk. There was no difference between aspirin and placebo periods in number of wheezing episodes, frequency of additional bronchodilator or prednisone use, or daily spirometric measurements. Serum thromboxane B2 levels were significantly reduced during aspirin therapy (p less than 0.001), indicating that the patients had complied with the aspirin therapy. Thus long-term administration of aspirin to asthmatics who show no immediate beneficial or adverse response to aspirin challenge appeared not to influence the clinical course of asthma. In addition, inhibition of the platelet prostaglandin cyclooxygenase pathway in these patients did not modify the clinical course of their asthma.     

A multicenter trial of the prophylactic effect of ketotifen, theophylline, and placebo in atopic asthma

Three hundred seventy-four patients with asthma were entered into a year-long, double-blind, double-placebo controlled study comparing the prophylactic effect of ketotifen (229 patients), theophylline (73 patients), and placebo (72 patients). The ketotifen group was larger to allow the accumulation of additional long-term safety data. The primary measure of therapeutic effect was a decrease in concomitant medication without a significant increase in symptomatology or a decrement in pulmonary functions. A patient daily diary was used to document symptoms (cough, shortness of breath, and wheeze) and concomitant medications taken during the 2-week baseline and the subsequent 12 monthly periods. After 2 months of study-drug therapy, the ketotifen patients had a greater decrease in both concomitant medication and symptomatology than either of the other groups. This delay in the onset of therapeutic activity has been observed in other studies and is characteristic of this compound. The principal side effect observed with ketotifen is initial sedation, which was found to be self-limiting and of little concern to the patient after the first month.     

The bronchodilator effect and pharmacokinetics of theobromine in young patients with asthma

The bronchodilator effect of a 10 mg/kg dose of theobromine (3,7-dimethylxanthine) was compared with that of 5 mg/kg of theophylline (1,3-dimethylxanthine) in young patients with asthma. Bronchodilation, as assessed by forced vital capacity, forced expiratory volume in the first second, forced expiratory flows at 25%, 50%, and 75% of vital capacity, and percent of forced expiratory volume in the first second/forced vital capacity did not differ significantly between the two drugs. After each drug bronchodilation peaked at 2 hours and lasted for 6 hours, although it was not always statistically significant for theobromine. The mean peak serum concentrations of both drugs, the time at which peak serum concentrations occurred, and elimination half-life values were similar for theobromine and theophylline.     

Timed effects of an oral adrenergic bronchodilator on pulmonary function and measurements of plasma and leukocyte cyclic AMP: divergence in duration of drug action and development of tolerance

The time course of response to initiation and withdrawal of treatment with terbutaline (5 mg orally, three times daily) was examined in eight normal subjects and 14 asthmatic patients. The various indices of response, examined simultaneously, yielded divergent estimates of the duration of drug action and the development of tolerance during continuous treatment. Bronchodilator responses were observed after each dose of terbutaline, but within 8 hr after a dose, pulmonary functions were similar to those observed in the absence of treatment. There was a suggestion of moderate tolerance to the bronchodilator effects of medication in that areas under the curve for increments in pulmonary function after terbutaline were lower during treatment than after the initial doses of medication; but the variations in magnitude of pulmonary response on different study days did not achieve statistical significance. Measurements of plasma cyclic AMP concentration suggested a much longer duration of drug action, with elevated levels observed 24 hr after a treatment dose; there was a progressive decrease in the plasma cyclic AMP responses to medication during the course of treatment. Conversely, leukocyte cyclic AMP responses to adrenergic stimulation were suppressed within 4 hr after the first dose of medication; the suppression persisted throughout treatment and for 1 to 3 days thereafter. These observations indicated that duration of drug action and induction of tolerance vary in different organ systems.     

Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children

The provocative dose of inhaled methacholine required to cause a 20% drop in the forced expiratory volume in 1 sec was evaluated in two selected pediatric populations. On the basis of a standardized respiratory questionnaire, 165 individuals 5 to 21 yr of age were identified. Included were 110 normal nonatopic individuals and 55 current asthmatic subjects. Methacholine inhalation challenges were performed by use of a standard inhalation procedure. Fifty-four (98.1%) of the asthmatic subjects responded to methacholine with a 20% drop in the forced expiratory volume in 1 sec. Seventy (63.1%) of the normal individuals did not respond to methacholine. The specificity and sensitivity of the methacholine challenge was best obtained at a provocative dose of 100 breath units of methacholine.     

Effect of montelukast on lung function in asthma patients with allergic rhinitis: analysis from the COMPACT trial

BACKGROUND: The Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) trial demonstrated that montelukast added to budesonide (MNT + BD) was as efficacious as double the dose of budesonide (dBD) in improving morning peak expiratory flow (AM PEF) in adult asthmatics. Recent studies have demonstrated that montelukast is also effective in treating daytime and nighttime allergic rhinitis (AR) symptoms in asthmatic patients. This analysis was designed to examine whether asthmatic patients with comorbid AR respond differently than patients without comorbid AR in terms of asthma control (lung function). METHODS: There were 216 asthmatic patients in the MNT+BD group and 184 patients in the dBD group with AR. Treatment differences in the change from baseline in AM PEF were compared. Least square (LS) mean and 95% confidence interval (CI) were derived from an anova model adjusting for baseline and study site. RESULTS: There was a 9.2% increase in AM PEF from baseline in the MNT+BD group compared with a 6% increase in the dBD group. The LS mean difference [(MNT+BD)-dBD] was 14.2 l/min (P=0.028). Other secondary endpoints were similar between groups. CONCLUSION: In the subgroup of asthmatic patients with AR, a combined treatment approach that included montelukast and budesonide provided significantly greater efficacy in reducing airflow obstruction compared with doubling the dose of budesonide. These results support recommendations by the Allergic Rhinitis and its Impact on Asthma initiative that suggest a unified approach aimed at treating the airway inflammation common to both diseases is beneficial for the large proportion of asthmatics who also suffer from AR.     

Airway responses to antigen challenge in allergic rhinitis and allergic asthma

The density dependence of the maximum expiratory flow-volume curve, functional residual capacity (FRC), and specific airway conductance (SGaw) were determined before and during bronchial provocation with ragweed extract in 27 subjects with ragweed hypersensitivity and a history of either bronchial asthma (16 subjects) or allergic rhinitis (11 subjects). Mean baseline SGaw was significantly lower while mean volume of isoflow (Visov) and FrC were significantly higher in subjects with bronchial asthma. During antigen challenge, 10 of 16 subjects with bronchial asthma (63%) and five of 11 subjects with allergic rhinitis (45%) showed a greater than 35% decrease in SGaw ("reactors"): mean relative decreases in SGaw from baseline were 46% and 53%, respectively. The remaining subjects showed a less than 35% decrease in SGaw ("nonreactors") with mean relative decreases of 9% (allergic asthma) and 6% (allergic rhinitis). Mean Visov increased in all subjects with bronchial asthma and in eight of 11 subjects with allergic rhinitis. A significant increase in FRC (6%) was seen only in the "reactors" with bronchial asthma. Following antigen challenge, the beta adrenergic agonist, isoetharine, increased SGaw and decreased Visov. We conclude that in asymptomatic subjects with ragweed hypersensitivity, (1) central and peripheral airway function is more abnormal in subjects with bronchial asthma than in subjects with allergic rhinitis, (2) subjects of both groups show quantitatively and qualitatively comparable airway responses during antigen challenge with a decrease in SGaw or an increase in Visov, possibly representing increase in central and/or peripheral airflow resistance, respectively, (3) Visov may be a more sensitive indicator of airway response to antigen challenge than SGaw, and (4) the bronchodilator effects of a beta adrenergic agonist on antigen-induced bronchospasm are similar in both groups.     

Bronchodilating effect of oral theophylline-ephedrine combination.

Ten adults with mild but continuously symptomatic asthma were compared with 10 nonsmoking normal persons. In Phase I after 2 wk without oral bronchodilators and 8 hr without aerosols, each subject received on five different days and in a randomized sequence either placebo, ephedrine 24 mg, theophylline 130 mg, theophylline + ephedrine, or theophylline + ephedrine +phenobarbital 8 mg. During Phase II, the 20 subjects took the theophylline-ephedrine-phenobarbital compound 4 times a day for 2 wk and continued this schedule for an additional 10 to 14 days while the five drug administrations of Phase I were repeated. The drug effects were evaluated by spirometry and flow volume loops and correlated and blood levels of theophylline. A single dose of the combination produced therapeutically useful bronchodilation of central and peripheral airways without producing much more frequent or severe side effects than either drug alone. The greater improvement that occurred by combining a low dose of theophylline with a low dose of ephedrine does not preclude a conclusion that similar improvement could have been achieved with a larger dose of theophylline. Addition of phenobarbital did not reduce symptoms of nervousness, tremor, or nausea. After 2 wk or longer of repeated doses, the combination produced about as much bronchodilation as after a single dose. Before the second set of measurements, theophylline levels had reached steady state after regular administration of 130 mg four times a day. Eight hours after the single dose, the mean serum level was 2.3 μg/ml; after 2 wk of repeated doses, 8 hr after a dose the mean was 5.3 μg/ml. Each drug, and the combination more than either, had a bronchodilating effect on small airways of normal subjects.     

Bronchodilatation and inhibition of allergen-induced bronchoconstriction by circulating epinephrine in asthmatic subjects

The influence of circulating epinephrine on basal bronchial tone and its ability to counteract the bronchial response to specific allergen challenge was investigated in eight patients with extrinsic seasonal asthma. A pretrial bronchial allergen challenge was positive for birch or timothy pollen. The patients were free from all medication at least 1 wk before experiments. On two separate occasions placebo (saline) or epinephrine (0.25 and 0.50 nmol X kg-1 X min-1) were infused. Epinephrine caused dose-dependent increases in end expiratory flow rates but did not influence peak expiratory flow rates or specific airway conductance, indicating dilatation of predominantly smaller airways. During placebo infusions allergen provocation induced clear-cut bronchoconstriction but no increase in circulating epinephrine levels. Elevation of circulating epinephrine (to 5 to 6 nmol/L in venous plasma) counteracted the allergen-induced bronchoconstriction. During epinephrine infusions all patients tolerated higher allergen doses than during placebo infusions. When the allergen dose was increased sufficiently to cause bronchoconstriction also during epinephrine infusions, the bronchoconstriction observed was similar in terms of changes in lung function parameters but less responsive to treatment with a high dose of the beta-2-agonist, salbutamol. This may have therapeutic implications since protection offered by treatment with, e.g. beta 2-agonists, may lead to exposure to higher allergen doses and similarly aggravated asthmatic reactions when they do occur despite this treatment.     

Relationship between types of asthmatic reaction,nonspecific bronchial reactivity,and specific IgE antibodies in patients with red cedar asthma

We studied the relationship between specific IgE antibodies, nonspecific bronchial reactivity to methacholine, and the type of asthmatic reaction in patients with red cedar asthma. The level of circulating specific IgE antibodies (expressed as RAST ratios) was not related to the type of asthmatic reaction, the degree of nonspecific bronchial hyperreactivity [expressed by the provocative concentration of methacholine producing a 20% decrease in the forced expiratory volume in 1 sec (PC₂₀)] or the index of reactivity to plicatic acid. On the other hand, methacholine PC₂₀ was found to correlate with the index of reactivity to plicatic acid in the late asthmatic reaction (LAR) and both the immediate and late components of the dual asthmatic reaction (DAR). Development of the LAR is associated with increase in nonspecific bronchial hyperreactivity. Repeated inhalation challenge with plicatic acid in eight patients with LAR resulted in DAR in all. The results suggest that the mechanism responsible for the LAR is associated with an increase in nonspecific bronchial reactivity; furthermore, the immediate component of DAR could also be related to heightened bronchial hyperreactivity.     

A controlled trial of real and simulated acupuncture in the management of chronic asthma

In 25 patients with moderate to severe asthma, we compared the therapeutic effectiveness of classic Chinese acupuncture with that of "placebo" acupuncture administered in a randomly ordered, subject- and evaluator-blind, crossover fashion twice weekly for 4 weeks. Real and placebo acupuncture periods were each preceded and followed by 3- to 4-week periods during which no acupuncture was administered. Outcome variables consisted of the following: daily symptoms and medication use self-scored on patient diaries, spirometry and whole body plethysmography performed once weekly during the entire course of the study and repeated serially during 3 hours after real and placebo acupuncture treatment, patients' self-assessment of acute efficacy of acupuncture therapy, and physician's physical findings before and after acupuncture treatment. Two-way analysis of variance failed to reveal a significant effect of either form of acupuncture on symptoms, medication use, or lung function measurements. Similarly, no significant acute effect of acupuncture on lung function, self-ratings of efficacy, or physician's physical findings was found by covariance analysis or the Wilcoxon signed-rank test. When data during the entire course of the study were examined on an individual basis by analysis of variance with repeated measures, only two subjects demonstrated significantly favorable responses to real versus placebo acupuncture, but one subject demonstrated the reverse, suggesting that these responses were not specifically related to acupuncture therapy. Thus, our findings failed to demonstrate any short- or long-term benefit of acupuncture therapy in the management of moderate to severe asthma.     

Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber

Allergen-induced late asthmatic responses are associated with an increase in bronchial responsiveness to histamine. We have examined the relationship between the magnitude of the late asthmatic response and the magnitude and duration of increased histamine responsiveness. Allergen inhalation tests were carried out in 12 asthmatic subjects to induce a mild early asthmatic response (16% to 40% reduction in FEV₁ in the first hour after allergen inhalation); the response was followed over 8 hr to identify the occurrence and magnitude of any late asthmatic response (maximum fall in FEV₁ from baseline between 3 and 8 hr). The provocation concentration of histamine causing a decrease in FEV₁ of 20% (PC₂₀) was measured before and after inhalation of allergen. The magnitude of decrease in PC₂₀ correlated with the magnitude of the late asthmatic response as measured by the percent fall in FEV₁ (r = 0.8, p < 0.002). The duration of decrease in PC₂₀ was from 2 to 74 days and this also correlated with the magnitude of the late response (r = 0.53, p < 0.05). Total lung capacity (TLC), residual volume (RV), FEV₁, maximal expiratory flow-volume curves (on air and He-O₂), and histamine responsiveness were also measured before and at intervals after allergen inhalation. Four of seven subjects still had a reduction in PC₂₀ when the TLC, RV, FEV₁, maximal expiratory flow-volume rates on air (V?₅₀air) and He-O₂ (V?₅₀He-O₂) (measured at an absolute volume corresponding plus 50% of control vital capacity) and ratio of V?₅₀He-O₂ to V?₅₀air were back t preallergen inhalation levels. In two of these subjects volume of isoflow was also back to ±10% of preallergen inhalation levels when the PC₂₀ was still significantly reduced. The results suggest that allergen-induced late asthmatic responses can be associated with an increase in bronchial responsiveness to histamine by mechanisms other than a reduction in baseline airway caliber alone.     

Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled trial

Background: Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control. Objective: Our purpose was to compare the efficacy and safety of salmeterol 50 μg combined with fluticasone 100 μg (in a combination dry powder product) with that of placebo, fluticasone, or salmeterol alone. Methods: A 12-week randomized, double-blind, multicenter study was conducted in 356 patients aged 12 years or older with asthma. After a 14-day screening period, patients were randomized to treatment with salmeterol 50 μg combined with fluticasone 100 μg (combination product), salmeterol 50 μg, fluticasone 100 μg, or placebo administered in the Diskus dry powder inhaler (GlaxoWellcome, UK) twice daily. Results: Mean change in FEV₁ at end point was significantly (P ≤ .003) greater with the combination product (0.51 L) compared with placebo (0.01 L), salmeterol (0.11 L), and flutica-sone (0.28 L). The combination product significantly increased (P ≤ .013) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo, salmeterol, and fluticasone at week 1 and week 12. Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups (P ≤ .020). The combination product significantly increased (P ≤ .012) morning PEF (combination, 52.5 L/min; placebo, –23.7 L/min; salmeterol, –1.7 L/min; fluticasone, 17.3 L/min) and evening PEF at end point compared with the other groups. The combination product significantly (P ≤ .025) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol. All treatments were equally well tolerated. Conclusion: Salmeterol 50 μg and fluticasone 100 μg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses. (J Allergy Clin Immunol 2000;105:1108-16.)