Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate.

OBJECTIVE: Intranasal beclomethasone dipropionate (BDP) has generally been considered to have no systemic activity at recommended doses, but the potential for long-term effects on growth has not previously been evaluated. This study was undertaken to assess the effects of 1 year of treatment with intranasal BDP on growth in children. STUDY DESIGN: In this double-blind, randomized, parallel-group study, 100 prepubertal children 6 to 9 years old with perennial allergic rhinitis were treated with aqueous BDP 168 microg twice daily (n = 51) or placebo (n = 49) for 1 year. Subjects' baseline heights were required to be between the 5th and 95th percentile, and skeletal age as determined by left wrist radiograph was required to be within 2 years of chronological age. Washout periods for medications known to affect growth, including other forms of corticosteroids, were established, and these medications were prohibited during the study. However, short courses of oral prednisolone lasting no more than 7 days, and short courses of dermatologic corticosteroids lasting no more than 10 days, were allowed. Height was measured with a stadiometer after 1, 2, 4, 6, 8, 10, and 12 months of treatment. The hypothalamic-pituitary-adrenocortical axis was assessed by measurements of 8 AM basal cortisol concentrations and response to. 25 mg cosyntropin stimulation. The primary safety parameter was the rate of change in standing height. Statistical analyses were based on all randomized subjects who received at least 1 dose of medication (intent-to-treat principle). The rate of change in standing height was analyzed for all subjects who entered the study and for those completing the full 12 months of treatment (n = 80). The rate of change in standing height over the 1-year study was calculated as the slope of a linear regression line fitted to each subject's height measurements over time. Because there was a statistically significant between-group difference in standing height at baseline, an analysis of covariance was performed for all analyses of standing height data. RESULTS: Of the 100 subjects enrolled, 90 completed the study. The 2 treatment groups were generally comparable at baseline; however, at baseline, mean age and mean height were significantly greater in the BDP treatment group that the in placebo treatment group. In both analyses, overall growth rate was significantly slower in BDP-treated subjects than placebo-treated subjects. The mean change in standing height after 1 year was 5.0 cm in the BDP-treated subjects compared with 5.9 cm in the placebo-treated subjects. The difference in growth rates was evident as early as the 1-month treatment visit, suggesting that the effect on growth occurred initially. The growth-suppressive effect of BDP remained consistent across all age and gender subgroups, and among subjects with and without a previous history of corticosteroid use. Use of additional exogenous corticosteroids during the study was similar in both groups and did not affect the results. Because there was a baseline imbalance in height, a supplemental analysis of the differences in prestudy growth rates was performed. This analysis found no baseline imbalance in prestudy growth rates. To determine whether the difference in growth rates during the study could be attributed to preexisting growth rates, a z score analysis was performed. The heights of both groups were normalized at baseline and at the end of the study using the US National Center for Health Statistics data for mean and standard deviations of height. This analysis confirmed that the difference in growth rates between the 2 groups was primarily attributable to the treatment rather than to any preexisting difference in growth. Additional analyses confirmed that the results were not influenced by outlier values. No significant between-group difference were found in the hypothalamic-pituitary-adrenocortical axis assessments. No unusual adverse events were observed. (ABSTRACT

Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

Onset and duration of action of levocabastine nasal spray in atopic patients under nasal challenge conditions.

BACKGROUND: Although prior studies have documented the rapid onset of action of topical intranasal levocabastine (LEV), little is known about its duration of action under nasal challenge conditions. OBJECTIVES: We sought to assess the onset and duration of action of escalating doses of LEV nasal spray by using a nasal allergen challenge (NAC) model. METHODS: Eighteen asymptomatic subjects with histories of seasonal allergic rhinitis were enrolled into a randomized, single-blind, placebo-controlled, dose-ranging crossover study. Each patient was randomly assigned to receive single doses of placebo and intranasal LEV 0.1, 0.2, and 0.4 mg during 2 parts of the study. In part 1 (onset of action), NAC consisted of a single dose of allergen administered 5 minutes after study drug treatment. In part 2 (duration of action), NAC consisted of increasing doses of allergen administered 0.5, 6, 12, and 24 hours on separate days after study drug treatment. Nasal symptom scores (NSSs) and nasal peak expiratory flow rates were measured after NAC in both phases of the study. Blood samples for plasma LEV concentrations were drawn after each NAC. RESULTS: In part 1, NSSs were significantly lower after the administration of LEV 0.1, 0.2, and 0.4 mg compared with placebo (P <.05). In part 2, NSSs were significantly lower after LEV doses of 0.2 and 0.4 mg compared with placebo at 0.5, 6, 12, and 24 hours after treatment (P <.05). The mean provocative dose of allergen required to elicit a positive nasal reaction was increased after LEV doses of 0.2 and 0.4 mg at 0.5, 6, and 12 hours after treatment. Nasal peak expiratory flow rates demonstrated no significant differences between LEV and placebo for any doses at any time points. Mean plasma LEV concentrations were low (range, 0 to 3. 7 ng/mL) after all doses and did not correlate with drug efficacy. CONCLUSIONS: Single intranasal LEV doses of 0.1, 0.2, and 0.4 mg significantly reduced the severity of the immediate nasal response to allergen when administered 5 minutes before NAC. This protective effect against NAC continued to be present 24 hours after administration of LEV doses of 0.2 and 0.4 mg. Efficacy in blocking the reaction to NAC did not correlate with plasma LEV levels, suggesting that the inhibitory effect was due largely to topical rather than systemic effects.

National guidelines needed to manage rhinitis and prevent complications.

OBJECTIVES: Rhinitis is an extremely common disease worldwide and nasal allergies are one of the major causes of the condition. Allergic rhinitis not only produces a range of nasal and non-nasal symptoms, but it has been closely associated with other chronic airways diseases, such as asthma and sinusitis. This review was undertaken to evaluate the relationship of allergic rhinitis to these diseases and to provide support for proposing national guidelines for managing rhinitis. DATA SOURCES: Relevant studies in English were searched for using MEDLINE, bibliographies from obtained articles, and consultation with experts. STUDY SELECTION: All major studies related to the epidemiology and effects of allergic rhinitis and the relationship between allergic rhinitis and asthma, sinusitis, and other airways diseases were reviewed. DATA SYNTHESIS: There is substantial scientific and clinical evidence that allergic rhinitis frequently coexists with asthma, and sinusitis and may be a predisposing factor for both. In addition, a number of studies have demonstrated that nasal inflammation and obstruction directly affect pulmonary function and clinical symptoms of asthma. Finally, it has been clearly demonstrated that treating allergic rhinitis with antihistamines, nasal corticosteroids, immunotherapy, and allergen avoidance have a significant, positive effect on lung function and asthma symptomology. CONCLUSIONS: The prevalence of allergic rhinitis, asthma, and sinusitis are increasing. Asthma and sinusitis can be debilitating conditions. Asthma alone can be life threatening and costly to treat. The timely and optimal treatment of allergic rhinitis may help prevent these conditions or, at least, prevent them from worsening. Consequently, there is an immediate need to establish national, evidence-based, practice guidelines to assist primary care physicians in diagnosing and managing rhinitis and in evaluating and managing rhinitis and in evaluating and managing allergic rhinitis coexisting with other airways diseases.

A comparison of triamcinolone acetonide MDI with a built-in tube extender and beclomethasone dipropionate MDI in adult asthmatics.

STUDY OBJECTIVE: In this study, the efficacy and safety of triamcinolone acetonide (TA) metered-dose inhaler with a built-in tube extender and beclomethasone dipropionate (BDP) metered-dose inhaler without a spacer device were compared. Both treatments were dosed at their most commonly used daily doses (within labeling). DESIGN: A 56-day, randomized, double-blind, double-dummy, placebo-controlled trial. SETTING: Seventeen asthma/allergy centers. PATIENTS: We enrolled 339 patients 18 to 65 years of age, with a documented history of bronchial asthma (FEV1, 50 to 90% of predicted value) for > or = 2 years who required inhaled corticosteroid therapy. INTERVENTIONS: Patients were randomized to receive BDP 336 microg/d (4 puffs bid) plus TA placebo (4 puffs bid), TA 800 microg/d (4 puffs bid) plus BDP placebo (4 puffs bid), or TA and BDP placebos (4 puffs of each bid). The only other asthma medication permitted was inhaled albuterol that was used as a rescue medication. All medications were administered via the closed-mouth inhalation technique. MEASUREMENTS AND RESULTS: At 8 weeks and at study end point, both active treatment groups had statistically significant and comparable improvements in FEV1 relative to baseline, and statistically significant increases relative to placebo. At study end point, improvements in forced expiratory flow (FEF25.75%), clinic peak expiratory flow (PEFR), and FVC were statistically significant for the active treatment groups compared with placebo. At end point, the mean difference between BDP and TA for mean change in FEV1 from baseline in the efficacy population was 0.02 and the 95% confidence interval was -0.11, 0.15. Asthma symptoms recorded at clinic visits showed statistically significant improvements for the BDP and TA groups compared with the placebo group. Treatment-related adverse events occurred with similar frequency in all patient groups-25.5% of placebo-treated patients, 22.3% of BDP patients, and 20.4% of TA patients. The incidence of oropharyngeal adverse events, including cough, thrush, and dysphonia, was not statistically different between the two active treatment groups. CONCLUSION: In this randomized, double-blind, placebo-controlled study of adult asthmatics treated with either BDP without a spacer or TA with its built-in tube extender, BDP and TA were comparable in efficacy as measured by FEV1 and other pulmonary function tests, and by improvement in asthma symptoms. Both active treatments were significantly more effective than placebo. All treatment groups were comparable in safety as measured by the incidence of adverse events.

Childhood asthma and allergic rhinitis: the role of leukotrienes.

Research in the past two decades has shown that patients with asthma and rhinitis have inflammation of the involved tissues. This perception has been reflected in recent treatment guidelines, which stress the decreased use of symptom-based therapy and increased use of antiinflammatory therapies to control underlying inflammation. Corticosteroids are the most effective drugs currently in use; however, their use may be limited by potential problems with safety and patient/family adherence, which includes the "fear factor." In addition, the use of high doses of topical corticosteroids (especially when used in both the nose and airways) may have adverse effects when used continuously for long periods. The inflammatory response is complex, involving numerous inflammatory mediators and cells that interact in complicated and interrelated pathways. This provides researchers with numerous interactions at which molecular intervention may result in the attenuation of inflammation, and thus clinical disease. The leukotrienes, a group of important inflammatory mediators, cause vascular leakage and tissue edema; they also promote mucus secretion and a potent bronchoconstriction in patients with asthma. Currently a number of antileukotriene drugs have been developed and preliminary research indicates that they may provide clinicians with a non-steroidal antiinflammatory therapy that may provide steroid-sparing effects. This review examines the leukotrienes and the effects of antileukotriene agents in patients with asthma and allergic rhinitis.

Improvement of bronchial hyperresponsiveness in asthmatic children treated for concomitant sinusitis.

BACKGROUND: There appears to be an association between sinusitis and asthma. The effect on bronchial hyperresponsiveness of clinical therapy for sinusitis in children may help to decipher whether sinusitis and asthma are independent manifestations of the same disease. OBJECTIVE: To evaluate the effect of clinical treatment for sinusitis in patients with rhinitis and/or asthma on symptoms and on bronchial hyperresponsiveness to methacholine. METHODS: Open label, randomized, non-treatment control in a teaching hospital in São Paulo, Brazil. Forty-six atopic and 20 normal children were studied. The atopic children consisted of 18 with allergic rhinitis (12 without sinusitis and 6 with sinusitis), and 28 children with rhinitis with asthma (13 with normal sinus radiographs and 15 with complete opacification of the maxillary sinuses). Methacholine PC20 was determined before and 30 days after treatment with nasal saline, sulfamethoxazole-trimethoprim, antihistamine/decongestant, and five days of prednisone. Sinus radiographs were also repeated. RESULTS: The only patients with increase in methacholine PC20 were patients with rhinitis and asthma with opacified maxillary sinuses at entry and who at 30 days had normal sinus radiographs (P < .05). CONCLUSION: In this study, children with allergic rhinitis and sinusitis with asthma improved their bronchial hyperresponsiveness to methacholine and decreased their symptoms with appropriate response of their sinuses to clinical therapy.

The effectiveness of once-daily dosing of inhaled flunisolide in maintaining asthma control.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of switching to once-daily (qd) administration of flunisolide in patients with asthma that was controlled by twice-daily (bid) dosing of this inhaled steroid. METHODS: Three hundred sixty-six adults and children with bronchial asthma that was controlled with inhaled steroids were recruited for this prospective, double-blind, parallel-group study. After a 4-week, stable baseline period of flunisolide administration, 2 inhalations (500 microg) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 microg) bid; group 2, 4 inhalations (1000 microg) qd in the morning; group 3, 4 inhalations (1000 microg) qd in the evening; or group 4, 2 inhalations (500 microg) qd in the morning. Outcome measures included morning and evening asthma symptoms (scale of 0 to 3), daytime and nighttime albuterol use, morning and evening peak expiratory flow rate (PEFR), FEV1, and methacholine PC20. In addition, a subset of patients in each group had 24-hour urinary cortisol levels measured before and after randomization. RESULTS: Outcome measures in the four groups were not significantly different at baseline before randomization. The three groups that received maintenance therapy with flunisolide, 1000 microg daily, did not show significant changes from baseline values and remained comparable in all outcome areas. Asthma control in the group randomized to flunisolide 500 microg qd, however, deteriorated significantly: morning symptoms increased by 0.21 units (48%), evening symptoms increased by 0.15 units (31%), daytime albuterol use increased by 0.42 inhalations per day (37%), nighttime albuterol use increased by 0.48 inhalations per night (91%), morning PEFR decreased by 17.1 L/min (4%), and evening PEFR decreased by 12.6 L/min (3%). There were no significant changes in PC20 or 24-hour urinary cortisol levels in any group. CONCLUSIONS: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 microg) bid, switching to 4 inhalations (1000 microg) qd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 microg) qd in the morning, however, leads to a deterioration in asthma control.

Organizing the community to target poor Latino children with asthma.

A community-university partnership to improve outcomes of care for poor Latino children (aged 6-14 years) with asthma in East Los Angeles was based on development of a community infrastructure. A family-centered educational program involved over 500 families. The Association of Latinos with Asthma and Allergy Symptoms (ALAAS) was formed. Parents report reductions in hospitalizations, emergency room, and acute care visits. Survival of the infrastructure following the end of grant funds is unlikely unless other resources offset the costs of volunteerism among poor families. Block grants to community agencies from established fund-raising groups might reduce dependency-producing practices currently employed to "help" the poor.

Helping patients live with asthma.

Few patients with asthma receive sufficient basic training in routine self-care. Even young children can learn to keep track of their symptoms, use a peak flow meter, and recognize when bronchodilator and anti-inflammatory drug dosages must be stepped up. Moreover, more than half of patients have chronic inflammatory airway disease, yet most of them are not being treated for the inflammatory component of their disorder.

Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma.

BACKGROUND: Many potential users of the H1 antihistamine cetirizine are asthmatic and may be using inhaled albuterol. This study was conducted to assess the possible bronchodilatory effect of cetirizine in patients with mild-to-moderate asthma and to determine whether cetirizine interacts with albuterol. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, the effects on pulmonary function of 5, 10, and 20 mg oral doses of cetirizine with and without inhaled albuterol (180 micrograms) were determined in 12 patients at 11 time points over 8 hours. The primary measure of efficacy was forced expiratory volume in 1 second (FEV1). RESULTS: Cetirizine with or without albuterol significantly increased FEV1, peak expiratory flow rate, and forced expiratory flow rate between 25% and 75% of vital capacity relative to baseline and placebo but did not have a significant effect on forced vital capacity. The effect of 20 mg of cetirizine on FEV1 was generally greater than that of 10 or 5 mg, but the difference was statistically significant only at the 30-minute time point (p < 0.05). All three cetirizine doses produced significantly greater increases than placebo in FEV1 and forced expiratory flow rate between 25% and 75% of vital capacity for 8 hours and in peak expiratory flow rate for 7 hours (p < 0.02). Albuterol alone had a significant effect on the four pulmonary function variables from 1 to 5 hours after baseline (p < 0.05), which is consistent with albuterol's recommended dosing frequency of every 4 to 6 hours. Albuterol alone increased FEV1 significantly more than 5 mg of cetirizine alone but not 10 mg or 20 mg of cetirizine alone at 60, 90, and 120 minutes after baseline, but all three doses of cetirizine increased FEV1 significantly more than albuterol 7 and 8 hours after baseline (p < 0.05), indicating that the bronchodilatory action of cetirizine lasts longer than that of albuterol. Cetirizine neither potentiated nor inhibited the bronchodilatory action of albuterol, but the two drugs appeared to have an additive bronchodilatory effect. None of the cetirizine treatments caused a worsening of pulmonary function, and all were well tolerated. CONCLUSIONS: Cetirizine has a significant bronchodilatory effect in patients with mild-to-moderate asthma and can be used to treat concomitant conditions (e.g., allergic rhinitis) without concern that it will interfere with the bronchodilatory effect of albuterol or cause worsening of asthma by itself.

A comparison of imaging techniques in patients with chronic sinusitis (X-ray, MRI, A-mode ultrasound).

Thirty-five patients age 9 to 67 were evaluated for chronic sinusitis by history, physical and laboratory examination, and imaging techniques (X-ray, magnetic resonance imaging (MRI) and flexible rhinoscopy). MRI was the most predictive. To establish the diagnosis of sinusitis, it was more sensitive than plain X-ray for intrasinus disease. Findings of edema, erythema, and drainage on flexible rhinoscopy were consistent with chronic sinusitis and were confirmed by MRI and sinus X-rays in 41% of the cases. Nasal smears for polymorphonuclear cells and eosinophils were suggestive of a diagnosis of chronic sinusitis, but other laboratory tests (CBC, sedimentation rate, quantitative immunoglobulins, total IgEs) were of very limited value in the diagnosis of chronic sinusitis.

Asthma update: new approaches and partnerships.

This article provides pediatric nurse practitioners with an update on new guidelines for the diagnosis and management of asthma. These guidelines, published in 1991 and 1992, are changing the way asthma is managed in the United States. The article highlights portions of the guidelines, with special emphasis on pediatric implications.

The termination of a randomized clinical trial for poor Hispanic children.

OBJECTIVE: To conduct a randomized clinical trial of the Spanish version of an educational program designed to be an adjuvant to adequate medical care of children with asthma. DESIGN: Randomized, clinical trial. SETTING: Los Angeles County, Calif. PARTICIPANTS: One hundred thirty-eight Hispanic children, ages 7 to 12 years, from disadvantaged families. All had used emergency facilities of major local hospitals in the previous year. MEASUREMENT/MAIN RESULTS: As the study proceeded, it became apparent that subjects were receiving inadequate medical and nursing care and had numerous barriers to applying knowledge and self-care skills gained from the program. Realizing this, we considered it unethical to allow the control children to suffer for the duration of the trial (1 year). Therefore, all children received "adequate" care from the research staff, and the randomized clinical trial, as originally designed, was ended. The emergency department/hospital use by both groups was significantly reduced compared with previous experience. CONCLUSION: Those researchers conducting randomized trials involving poor children should be aware of the potential ethical problems inherent in such ventures.

Validity and reproducibility of multi-test skin test device.

Thirty patients were skin tested by Multi-Test and Morrow Brown needle using antigens, histamine, glycerosaline, and blank controls to examine reproducibility and influence of positive reactions on adjacent negative controls. There was no evidence that histamine or strongly positive antigen reactions affected adjacent negative controls. Multi-Test was more reproducible, and preferred by patients over Morrow Brown.

An update on the diagnosis and management of pediatric asthma. Based on the National Heart, Lung and Blood Institute expert panel report.

Asthma morbidity and mortality are increasing despite the availability of antiasthma medicines and a broader understanding of the pathology of the disease. In an attempt to enhance the understanding of asthma and to aid in appropriate asthma management, the National Heart, Lung and Blood Institute assembled an expert panel, which developed a report titled "Guidelines for the Diagnosis and Management of Asthma." These guidelines are designed to facilitate patient and health-care-provider education, and diagnosis and management of asthma. Proper diagnosis of the disease is a frequent problem in children and adults. For proper diagnosis of asthma, a complete patient history, physical examination and specific laboratory tests are required. Health care providers who educate patients and their families about common symptom triggers, encourage avoidance techniques and who incorporate state-of-the-art treatment for acute and chronic asthma management may reduce the recent increases in asthma morbidity and mortality while maintaining normal growth and development of the child.