In Reply.— Dr Altenburger's letter asks us to go beyond our statement endorsing medical therapy for a child with exercise-induced asthma into a statement about what "schools should" and "should not" do about medications. It has always been difficult for the "little white clinic" to tell "the little red schoolhouse" how to handle health concerns. It should be recognized that in some communities there is very good communication and cooperation and that policy statements cannot assure such good practice.
Azelastine is a novel antiallergy medication currently under investigation for the treatment of allergic rhinitis and asthma. Pharmacologic studies in laboratory animals and in vitro model systems indicate that azelastine exerts multiple actions including modulation of airways smooth muscle response, interference with inflammatory processes, and inhibition of allergic reactions. In a previous controlled clinical trial, azelastine nasal solution (ASTELIN N.S.™) demonstrated effectiveness in controlling symptoms of seasonal allergic rhinitis (SAR). The objective of this 2-week double-blind, parallel-group study was to further assess the effectiveness of azelastine nasal solution in improving allergic rhinitis symptoms. Two hundred forty-seven patients (≥12 years) with symptomatic SAR who satisfied a minimum symptoms score during a 1-week, single-blind, baseline evaluation period were randomized to receive azelastine 2 sprays per nostril bid, azelastine 2 sprays per nostril qd, chlorpheniramine 12 mg bid, or placebo using a double-dummy technique to insure blinding. The primary efficacy variables were changes in Major Symptom Complex (nose blows, sneezes, runny nose/sniffles, itch nose, and watery eyes) and Total Symptom Complex (Major plus itchy eyes/ears/throat/palate, cough, and postnasal drip) severity scores. Patients treated with azelastine nasal solution qd and bid had mean percent improvements in the Total and Major Symptom Complex severity scores that were clinically significant (≥50% improvement over placebo) after both weeks, at endpoint, and overall. The improvements for the azelastine bid group were statistically significant (P≤.05) at all evaluation points. Adverse experiences occurred infrequently, and none was considered serious or potentially limiting to the clinical utility of the nasal solution. The favorable safety profile of azelastine nasal solution together with its rapid onset and prolonged duration of action in relieving rhinitis symptoms and advantages over currently marketed topical treatments make it a good choice for treatment of SAR. The results of this trial demonstrate that azelastine nasal solution provides an alternative to oral medication in the treatment of SAR.
The p-nitrophenyl ethyl phosphonate esters have been shown to inhibit complement-dependent erythrophagocytosis when exposed to guinea pig polymorphonuclear leukocytes prior to the initiation of phagocytosis. Inhibition of phagocytosis occurred in a manner characteristic of the well-defined capacity of phosphonate esters to inactivate serine esterases: inhibition was irreversible, dependent upon the temperature of reaction and pH of the reaction medium, and proportional to the concentration of inhibitor used and the duration of exposure between leukocytes and inhibitor. Phosphonate inhibition was further shown to be independent of any general cell damaging effects of the compounds used. The phagocytic enzyme inhibited by phosphonate esters apparently exists in or on leukocytes in an already activated state prior to the initiation of the phagocytic process. The inhibitory profile of the activated phagocytic esterase was found to be essentially identical to the profile of inhibition previously obtained for the activated chemotactic esterase of rabbit polymorphonuclear leukocytes, suggesting that the same enzyme may function in both chemotaxis and phagocytosis. Various substrates including acetate esters reported to protect the activated chemotactic esterase from inhibition by phosphonate esters did not exhibit a clear protective effect in the phagocytic system and attempts to define the relationship between the two enzymes were unsuccessful. Suggestive evidence was also obtained for the requirement of the function of a second, activatable esterase in the phagocytic process.
Objective. Intranasal corticosteroids are used widely for the treatment of allergic rhinitis because they are effective and well tolerated. However, their potential to suppress growth of pediatric subjects with allergic rhinitis continues to be a concern, particularly in light of reports of growth suppression after treatment with intranasal beclomethasone dipropionate or intranasal budesonide (see the article by Skoner et al in this month's issue). A 1-year study of prepubertal patients between 3 and 9 years of age with perennial allergic rhinitis was conducted to assess the effects on growth of mometasone furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal corticosteroid with negligible bioavailability. Methods. This was a randomized, placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were randomized to treatment with either MFNS 100 μg QD or placebo for 1 year. Each subject's height was required to be between the 5th and 95th percentile at baseline, and skeletal age at screening was required to be within 2 years of chronological age, as determined by left wrist x-rays. Washout periods for medications that affect either childhood growth or allergic rhinitis symptoms were established based on estimated period of effect, and these medications were prohibited during the study. However, short courses of either oral prednisone lasting no longer than 7 days or low-potency topical dermatologic corticosteroids lasting no longer than 10 days were permitted if necessary. Height was measured with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks, and the primary safety variable was the change in standing height. The rate of growth was also calculated for each subject as the slope (linear regression) of the change in height from baseline using data from all visits of subjects who had at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks. All analyses were based on all randomized subjects (intent-to-treat principle). The change from baseline in standing height was analyzed by a 2-way analysis of variance that extracted sources of variation attributable to treatment, center, and treatment-by-center interaction. Results. Demographic characteristics were similar at baseline. Eighty-two subjects completed the study (42 in the MFNS group and 40 in the placebo group), and 93% of subjects achieved at least 80% compliance with therapy. After 1 year of treatment, no suppression of growth was seen in subjects treated with MFNS, and mean standing heights were similar for both treatment groups at all time points. For the primary safety variable (change in height from baseline), both treatment groups were similar at all time points except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean increase in height than subjects treated with placebo at these time points: the change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However, the rate of growth (.018 cm/day) averaged for all time points over the course of the study was similar for both treatment groups. Additional analyses found that MFNS did not retard growth in any sex or age subgroup of subjects. The use of exogenous corticosteroids other than the study drug was also similar among the 2 treatment groups. Results from cosyntropin stimulation testing confirmed the absence of systemic effects of MFNS. The change from baseline in the difference between prestimulation and poststimulation levels was similar for both treatment groups after 1 year of treatment, with no evidence of HPA-axis suppression in MFNS-treated subjects at any time point. Incidences of treatment-related adverse events were similar for both treatment groups, with 16% of MFNS-treated subjects reporting adverse events, compared with 22% of placebo-treated subjects. Conclusions. In summary, 1 year of treatment with MFNS 100 μg QD was found to be well tolerated, with no evidence of retardation of growth or suppression of HPA-axis function in perennial allergic rhinitis subjects as young as 3 years of age. These findings may be particularly relevant for children with co-morbid atopic disorders, such as asthma and eczema. Such patients may be treated concurrently with inhaled and/or dermatologic corticosteroids, thereby increasing the risk of systemic adverse events, including growth suppression. The absence of systemic adverse events found in this study, combined with the established efficacy and safety profile of MFNS in children, indicates that it may be an appropriate therapy for children as young as 3 years of age.3,4
Background. A powder formulation of salmeterol has been shown to prevent exercise-induced bronchospasm (EIB) in asthmatic children and adults; however, the delivery device (Diskhaler; Glaxo Wellcome Inc, Research Triangle Park, NC) must be reloaded after 4 doses. A new multidose powder inhaler (Diskus) provides 60 doses of salmeterol in a blister pack presentation with a dose counter. Objective. To evaluate the safety and efficacy of 50-μg salmeterol powder via two different delivery systems (Diskhaler and Diskus) in preventing EIB in asthmatic children. Study Design. A randomized, double-blind, double-dummy, single-dose, placebo-controlled, three-way crossover study was conducted in 24 children 4 to 11 years of age demonstrating EIB and mild to moderate asthma. Serial forced expiratory volume in 1 second (FEV1) was measured before and after treadmill exercise challenges conducted at 1, 6, and 12 hours after study drug administration. Adverse events were also assessed. Results. During all exercise challenges, EIB-mediated reductions in FEV1 were minimized or prevented in patients receiving single doses of salmeterol powder compared with placebo. Single doses of salmeterol powder delivered via either system were equally effective in preventing EIB. There were no drug-related adverse events, cardiovascular, or other clinically relevant safety concerns. Conclusions. Single doses of salmeterol powder delivered by either delivery system are safe and effective in preventing EIB for ≥12 hours in asthmatic children.
The relationship between allergy and croup is examined addressing possible associations between croup and IgE antibody production, and between croup and atopic allergic disorders irrespective of the presence or absence of IgE antibody. A case can be made for an increased association between allergy and recurrent croup. Children with croup are more likely to produce IgE antibodies than normal children without croup and there is an association between the production of IgE antibody to certain respiratory viral infections and the development of croup. There also is an increased association between croup, asthma and nonspecific bronchial hyperresponsiveness associated with asthma.
Background In previous clinical trials, cetirizine has been shown to be efficacious in the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis, and chronic idiopathic urticaria when given once daily. As significant QT prolongation and cardiac arrhythmias have been reported with some of the newer antihistamines, the electrocardiographic effects of cetirizine were evaluated. A previous study in normal, healthy, adult volunteers had demonstrated that cetirizine does not prolong the QT interval at up to six times the maximum clinical dose. Objective The intent of this study was to evaluate the electrocardiographic effects of cetirizine in children. Methods and Patients As part of a randomized, 4-week, controlled clinical trial, electrocardiograms (ECGs) were obtained for 119 children aged 6 to 11 years with SAR. Participants in this trial received either a placebo (N = 40), 10 mg of cetirizine (N = 44), or 5 mg of cetirizine (N = 35). The QT interval was measured on a 12-lead ECG at the baseline visit (day 1) and at visit 2 (days 11-17). The QT interval was determined by a digitizing method and corrected for heart rate by the Hodges' formula for corrected QT interval (QTc). Results Five and 10 mg of cetirizine did not result in changes in the QTc interval that were significantly different statistically from those of a placebo. Furthermore, the number of patients with a 10% to 20% increase in QTc interval was comparable across all treatment groups. Finally, no patients had a QTc interval increase of greater than 20% from baseline. Conclusions The study demonstrates that cetirizine, up to 10 mg once daily, did not prolong the QTc interval in pediatric patients with SAR.
Background: The dry powder inhaler (DPI) device for budesonide inhalation powder 200 μg (DPI‑A*) was redesigned to improve dosing consistency and provide new features (budesonide inhalation powder 90 μg and 180 μg; DPI‑B†).Objective: Two multicenter, parallel-group, double-blind, randomized, 12-week studies compared the efficacy and safety of budesonide delivered via each DPI versus placebo, and the systemic exposure of budesonide from each device.Methods: Asthmatic adults with mild-to-moderate asthma (N = 621) and patients 6–17 years with mild asthma (N = 516) received budesonide DPI‑B 360 μg or DPI‑A 400 μg twice-daily (total daily dose 720 μg or 800 μg), budesonide DPI‑B 180 μg or DPI‑A 200 μg once daily (total daily dose 180 μg or 200 μg), or matching placebo. Change in forced expiratory volume in 1 second (FEV1) and secondary variables (asthma symptoms, β2-adrenergic agonist use, peak expiratory flow [PEF], and withdrawals due to worsening asthma) versus placebo were measured.Results: In both studies, FEV1 significantly ( p < 0.05) improved for all active treatments versus placebo except once-daily budesonide DPI‑B 180 μg in adults. In the adult study, significantly ( p < 0.05) greater improvements in all secondary variables occurred with all active treatments versus placebo. In the pediatric/adolescent study, improvements in AM/PM PEF were significantly (p ≤ 0.011) greater with twice-daily budesonide DPI‑B 360 μg versus placebo. Numerically fewer patients in all active-treatment groups withdrew due to worsening asthma versus placebo.Adverse event profiles were similar among groups. In the pediatric/adolescent study, no significant differences in mean 24-h urine cortisol or cortisol : creatinine ratio assessments were observed between the active treatment groups and the placebo group. Although pharmacokinetic variables were generally similar across subgroups in the adult (n = 77) and pediatric/adolescent (n = 32) studies, pairwise treatment comparisons of twice-daily budesonide DPI‑B 360 μg versus DPI‑A 400 μg and once-daily budesonide DPI‑B 180 μg versus DPI‑A 200 μg showed large variability for the area under the drug plasma concentration–time curve over the dosing interval and the maximum detected drug plasma concentration.Conclusions: The efficacy and safety of budesonide DPI‑A and DPI‑B versus placebo were demonstrated across the low to medium inhaled corticosteroid dose range in children ≥ 6 years with very mild asthma and adolescents and adults with mild-to-moderate asthma. The study is limited by the evaluation of only two doses for each product in both studies. Additionally, the studies were not designed to test equivalence or noninferiority between the active products. Pharmacokinetic characterization was limited because of the small sample sizes.
