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This case report demonstrates a small repetition of the case series carried out in Italy wherein inhaled adenosine was administered to patients experiencing severe and worsening coronavirus disease-2019 (COVID-19). The two cases are important not only because they were the first of their type in the United States, but also because both patients were DNR/DNI and were therefore expected to die. Study repetition is vitally important in medicine. New work in pharmacology hypothesizes that adenosine-regulator proteins may play a role in the pathogenesis of COVID-19 infection. Furthermore, adenosine, by interacting with cell receptor sites, has pluripotent effects upon inflammatory cells, is anti-inflammatory, and is important in tissue hypoxia signaling. Inhaled adenosine is potentially safe; thousands have received it for asthmatic challenge testing. The effects of adenosine in these two cases were rapid, positive, and fit the pharmacologic hypotheses (as seen in prior work in this journal) and support its role as a therapeutic nucleoside.

BACKGROUND AND OBJECTIVES: The albuterol dropper bottle used to prepare solutions for continuous nebulization contains the preservative benzalkonium chloride (BAC). BAC, by itself, has been shown to cause bronchospasm. We hypothesized that BAC would decrease the therapeutic efficacy of albuterol in patients with acute asthma exacerbations. METHODS: We performed a retrospective cohort study comparing the clinical outcomes of patients RESULTS: A total of 477 patients were included in the analysis (236 exposed to BAC and 241 controls). The duration of continuous nebulization was significantly longer in the BAC group than in the control group (median of 9 vs 6 hours; 15.7% required continuous nebulization compared to 5.8% of controls at 24 hours). The control group was 79% more likely to stop continuous nebulization at any particular point in time (hazard ratio 1.79; 95% confidence interval: 1.45 to 2.22; P < .001) and 43% more likely to stop additional respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001). CONCLUSIONS: BAC is a functional albuterol antagonist associated with a longer duration of continuous albuterol nebulization treatment and additional respiratory support, suggesting that preservative-free albuterol formulations are safer for use in continuous nebulization.

Background: Poor adherence with inhaled corticosteroid (ICS) medication is common in the pediatric population and can result in poor asthma control with increased frequency of asthma-related complications. The purpose of this study was to determine whether or not the initiation of ICS administration twice per day at school/daycare in patients with poor medication adherence at home improves asthma health care outcomes. Methods: We retrospectively selected patients followed by our Pediatric Pulmonology Clinic who had poorly controlled asthma and had been assigned to receive ICS twice daily at school/daycare due to poor adherence with ICS therapy. We analyzed the number of short courses of oral corticosteroids, hospital admissions, emergency department visits, and intramuscular methylprednisolone administrations for asthma exacerbations for the year before and after the intervention. The Wilcoxon signed rank test with continuity correction was used in the primary analysis. Results: Forty-nine patients who met the inclusion criteria were identified, but only 40 actually started the intervention. The number of oral corticosteroid courses per year decreased from 1.35 ± 1.1 before the intervention to 0.68 ± 1.2 (P = 0.008) postintervention, hospital admissions per year decreased from 0.45 ± 0.7 to 0.10 ± 0.3 (P = 0.006), emergency department visits per year decreased from 0.55 ± 0.8 to 0.28 ± 0.6 (P = 0.084), and intramuscular repository methylprednisolone injections per year for asthma exacerbations decreased from 0.20 ± 0.4 to 0.10 ± 0.3 (P = 0.23). Conclusion: These results indicate that school/daycare administration of ICS may be an effective option to improve indicators of asthma exacerbations in children with poor adherence to ICS at home.

For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.

Summary Background Bronchoprovocation with methacholine (MC) is the most sensitive method of determining bioequivalence of inhaled bronchodilators. FEV1 is used to determine the endpoint, but many children cannot perform spirometry reproducibly. The purpose of this study was to determine whether MC, using impulse oscillometry (IOS) as the endpoint, can differentiate between two doses of salmeterol (SM). Methods This was a single-blind, randomized study of 10 subjects with mild stable asthma, ages 4–11 years. None were taking a long-acting β-agonist but most were on low-dose inhaled corticosteroid. On one study day, MC was performed 1 hr after one inhalation from each of two separate Advair 100/50 Diskus (100 μg salmeterol treatment). On a second day, MC was performed after one inhalation from Advair Diskus and one inhalation from Flovent Diskus 100 (50 μg salmeterol treatment). The provocative concentration of methacholine causing a 40% increase in total airway resistance (PC40R5) was calculated. Results The reduction in R5 (bronchodilator effect) was 15.5% and 18.4% for 50 and 100 μg, respectively (NS). After MC (bronchoprotective effect), the geometric mean (95%CI) PC40R5 (mg/ml) was 2.4 (1.3–4.4) during screening, 22.9 (8.5–61.6) after 50 μg SM and 47.0 (25.2–87.8) after 100 μg SM (P = 0.051 for 50 vs. 100 using a linear mixed effects model). No adverse effects were observed. Conclusions MC with IOS endpoint will be a useful method for determining bioequivalence of a generic inhaler in children. Seventy-two subjects will be required to achieve 80% power to assess bioequivalence of SM. Pediatr Pulmonol. © 2015 Wiley Periodicals, Inc.

This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted. Subjects attended a clinic visit daily on consecutive mornings during each of 3 1-week treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 fluticasone propionate/salmeterol combination product (Advair® Diskus). Daily eNO value recorded was the highest of 3 measurements; 1 inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washouts. A total of 105 subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percentage eNO decrease (standard deviation) from day 1 baseline for each treatment period was 36.6 (±18.7), 45.3 (±16.5), and 54.6 (±12.5) with Advair® 100/50, 250/50, and 500/50, respectively. Mean percentage decrease in eNO across each treatment (dose) was modeled using a mixed-model ANOVA. Although the overall treatment was significant (P = .0015), because of the relatively small sample size and within-subject variability, only the 100/50 vs 500/50 (P = .0003) and 250/50 vs 500/50 (P = .047) treatments were significantly different.

In 2006, the US FDA issued a ‘Guidance for Industry’ regarding submission of New Drug Applications for pancreatic enzyme replacement therapy (PERT) products. Five oral delayed-release PERT products have been approved by the FDA, and several others are under development and/ or evaluation for New Drug Application submission. We present in this paper recommendations of the Cystic Fibrosis Foundation's Cystic Fibrosis (CF) Therapeutics Development Network and Data Safety Monitoring Board regarding study design considerations for evaluating PERT products in patients with CF. Careful attention to study design and accuracy of the outcome measures has confirmed our understanding of the efficacy and safety of PERT for the treatment of exocrine pancreatic insufficiency of CF.

Delivery of inhaled medications to children with asthma by a small-volume nebulizer is an antiquated method. Delivery by metered dose inhaler through a valved holding chamber with mask is at least equally effective, but more convenient, safer, faster, and less expensive. In addition, antistatic chambers increase the amount of drug delivered to the airways. This is an advantage for albuterol, but could increase the risk of long-term systemic adverse effects of inhaled corticosteroids at higher doses.

Omalizumab is a recombinant DNA-derived humanized immunoglobulin G (IgG) anti-IgE monoclonal antibody approved for use in patients with allergic asthma. However, it is not approved for allergic bronchopulmonary aspergillosis (ABPA). Conflicting reports exist about the effects of omalizumab on ABPA in patients with cystic fibrosis (CF). We report 2 patients with CF treated with omalizumab, in whom frequency of ABPA exacerbations was markedly reduced with treatment. Additionally, hospitalizations were reduced from 5 per year to once in 18 months in the first patient and from twice to once per year in the second patient. Free IgE decreased by 87.9% after 6 months of therapy in the first patient and by 95.6% after 7 months of therapy in the second patient. Neither of the two patients had evidence of asthma. Omalizumab may be useful in treating ABPA in patients with CF, and including free IgE in monitoring the response to therapy will be helpful.

BACKGROUND We sought to compare the differences of coefficient of fat absorption (CFA) and coefficient of nitrogen absorption (CNA) in healthy individuals and those with cystic fibrosis (CF) and to study the precision of CFA and CNA.METHODS Sixteen healthy and 23 subjects with CF and pancreatic insufficiency ate a high-fat, high-protein diet for 72 hours; stool was collected between blue food dye markers to determine CFA and CNA. Subjects with CF withheld pancreatic enzymes. Tests were repeated on 5 of the CF and 10 of the healthy subjects.RESULTS In healthy subjects, mean CFA was 93.5% ± 2.7%; mean CNA was 88.1% ± 5%. Median test-retest in 10 healthy subjects was +0.7% CFA (range, −8.1% to + 5.9%) and +0.9% CNA (range, −14.6% to +6.8%). For subjects with CF, mean CFA was 38.5% ± 14.7% and mean CNA was 52.2% ± 11.4%. Median test-retest change in 5 subjects with CF was −6.9% CFA (range, −19.7% to +42.8%) and +14.7% CNA (range, −6.4% to +42.8%).CONCLUSIONS CFA and CNA have inconsistent precision in CF. The limitations of CFA as a measure of steatorrhea correction in CF should be recognized in studies of pancreatic enzyme supplements.

Objective To determine whether an antistatic valved holding chamber/mask improves lung bioavailability of hydrofluoroalkane (HFA) fluticasone in young children. Study design Twelve patients, age 1 to 6 years, with well-controlled asthma were treated with an HFA fluticasone metered-dose inhaler (Flovent HFA) twice daily (440 μg/day). The drug was delivered by tidal breathing through conventional (AeroChamber Plus) and antistatic (AeroChamber MAX) valved holding chambers (VHCs) with masks in a randomized, crossover manner, each for 3 to 7 days. When adherence was 100% at home, blood was collected for measurement of steady-state fluticasone plasma concentration (FPC) 1 hour after the last dose was administered in the clinic. FPC indicates systemic exposure directly and airway delivery indirectly. It was measured by liquid chromatography-mass spectrometry. Data were analyzed by regression analysis. Results The mean ± SD FPC was 107 ± 30 pg/mL after conventional VHC and 186 ± 134 pg/mL after the antistatic VHC (P = .03). In 5 patients (40%), the antistatic VHC increased FPC by ≥ 100%, to potentially excessive levels in 4 of them; it had little effect in 7 patients. Conclusions HFA fluticasone was delivered to the airways by both devices even though the patients could not inhale deeply and breath hold. The antistatic VHC variably increased lung bioavailability. To reduce systemic exposure, the dose should be weaned to the minimum required to maintain asthma control.

Use of recommended IV aminophylline dosage regimens in 48 older, acutely ill, hospitalized patients with chronic obstructive pulmonary disease (COPD) resulted in excessive plasma theophylline concentrations in 29 percent of these patients. A mean dose of 0.89 mg/kg/hr produced a plasma concentration which ranged from 7 to 52 mcg/ml with a mean of 21.9 mcg/ml. Plasma theophylline concentration was determined spectrophotometrically from plasma samples drawn at least 12 hours after a loading dose and initiation of a constant infusion. Severity of toxicity strongly correlated with the plasma theophylline concentration in 18 patients. Nausea and/or vomiting preceded life-threatening drug-induced arrhythmias and seizures less than half the time. Tachycardia was found to be the most consistent symptom associated with toxicity. These patients had lower plasma clearances than otherwise healthy younger adult asthmatics and healthy volunteers. Toxicity and identifiable risk factors for excessive plasma levels strongly correlated with reduced plasma clearance. Dosage modifications based upon plasma clearances from COPD patients without concurrent functional abnormalities and those with liver dysfunction and cardiac decompensation ranged from 0.7 to 0.12 mg/kg/hr. This study clearly demonstrates the poor correlation between dose and plasma concentration and the strong relationship between toxicity and plasma concentration. These results as well as those previously reported mandate that the relatively simple, rapid and inexpensive theophylline plasma measurement be used in all patients receiving IV aminophylline for longer than 24 hours in order to prevent toxicity.

Purpose. Evidence supporting the delivery of bronchodilators with a metered-dose inhaler and a valved holding chamber (MDI+VHC) in place of a small-volume nebulizer (SVN) is discussed, and the steps taken to accomplish such a conversion program at one institution are described. Summary. Double-blind, randomized studies in patients with acute exacerbations of asthma have demonstrated that higher doses of albuterol delivered by MDI+VHC (4–10 puffs per dose) are as effective as 2.5 mg of albuterol sulfate delivered by SVN. Three double-blind studies support the conclusion that the two methods are equivalent with respect to both efficacy and adverse effects in patients with chronic obstructive pulmonary disease. MDI+VHC offers practical advantages over SVN, including the capacity for home use by the patient, portability, less setup time, and no need for daily disinfection. Pharmacists and respiratory therapists obtained approval through the pharmacy and therapeutics committee for respiratory therapists to convert orders for bronchodilators delivered by SVN to administration by MDI+VHC. The conversion policy allows physicians to override it, but none have exercised this option. On intensive care units (ICUs), the policy resulted in a 53% increase in the use of MDI+VHC during the six-month period after it went into effect. Respiratory therapists have been less thorough in implementing the policy for non-ICU patients. Conclusion. Delivery of bronchodilators by MDI+VHC is as effective as delivery by SVN but offers several advantages. A policy to switch patients from SVN to MDI+VHC for bronchodilator administration met with limited success.

Background During conventional daytime studies of β 2 -agonists, 1 puff of a metered-dose inhaler often produces a near maximum bronchodilator response. Consequently, the US Food and Drug Administration–approved dose of albuterol is only 1 to 2 puffs every 4 to 6 hours. Objective To determine whether a higher dose of albuterol is required to normalize lung function during nocturnal asthma. Methods Fifteen subjects (age, 18-37 years) were treated with albuterol metered-dose inhalers in a randomized crossover manner at the onset of nocturnal symptoms while sleeping in the Clinical Research Center and during the day when they were asymptomatic. The dose was doubled at 15-minute intervals to 16 cumulative puffs. Results The mean ± SD predose FEV 1 was lower at night than during the day (44% ± 12% vs 68% ± 9% predicted; P = .0001). The maximum FEV 1 achieved was also lower at night (84% ± 15% vs 90% ± 12%; P = .02). The nocturnal dose-response curve was shifted to the right. The median (25th, 75th percentiles) dose required to achieve 80% of the subject's personal best FEV 1 was substantially higher at night (5 [1, 19] vs 0.4 [ P = .02), and the median time to achieve this endpoint was longer (47 [21, 90] vs 10 [0.2, 42] minutes; P = .005). No significant systemic effects were observed. Conclusion At night, the response was slower and required a higher dose because more severe airway obstruction was present on awakening. These results suggest that studies establishing the clinical dose of a β 2 -agonist or assessing the equivalence of different formulations should be conducted in subjects with more severe reversible airway obstruction than is present during conventional daytime studies.

Study objectives Recent American Thoracic Society guidelines recommend two different methods of methacholine challenge testing: the 2-min tidal breathing method with twofold increases in concentration, and the five-breath dosimeter method with fourfold increases. Since the tidal breathing method delivers more methacholine to the mouthpiece, we hypothesized that the provocative concentration of methacholine required to decrease FEV 1 by 20% (PC 20 ) would be lower than with the dosimeter method. Design Twelve subjects 18 to 45 years old with stable asthma were selected on the basis of a screening PC 20 (by tidal breathing) of Results The geometric mean PC 20 was 1.8 mg/mL (95% confidence interval [CI], 0.7 to 4.3) after tidal breathing and 1.6 mg/mL (95% CI, 0.7 to 3.7) after dosimeter (p = 0.2). There was no significant difference between the screening PC 20 and the PC 20 obtained by either method on randomized study days. The maximum decrease in FEV 1 from diluent baseline after the last concentration was 27.8% (range, 20 to 50%) during tidal breathing and 27.9% (range, 16 to 47%) during the dosimeter method (p = 0.35). Conclusions Both methods give similar results. Fourfold increases in methacholine concentration with the dosimeter method are as safe as twofold increases with the tidal breathing method.

Bronchospasm precipitated by exercise is often indistinguishable from bronchospasm produced by other stimuli. Symptoms result from airflow limitation and include wheezing, cough, chest tightness, dyspnea and sometimes hypoxemia. The prevalence of exercise-induced bronchospasm varies from 30%-90%, but virtually all patients with current asthma will experience a decrease in lung function if the exercise is sufficiently vigorous, especially in cold, dry environmental conditions. Exercise-induced bronchospasm is more prevalent in children than in adults, probably because children are physically more active. It is also more prevalent among elite winter sports athletes. The pathogenesis of exercise-induced bronchospasm involves a defect in respiratory heat exchange that probably triggers mast cell and eosinophil release of bronchoconstricting mediators. The goal of therapy is prevention of symptoms. This may be accomplished by pre-treating patients with isolated exercise-induced bronchospasm using an inhaled rapid-onset β2-adrenergic agonist before a scheduled activity or by treating the underlying inflammation when exercise-induced bronchospasm is part of the clinical syndrome of persistent asthma. In the later instance, either an inhaled corticosteroid, an oral leukotriene modifier, or a combination of both, depending on severity, may be required to prevent exercise-induced bronchospasm associated with activities of daily living. In addition, some of these patients may still require pre-treatment with a short-acting inhaled β2-agonist before a scheduled vigorous activity, especially in very cold ambient temperatures. Because the duration of bronchoprotection decreases with daily use (tachyphylaxis), long acting β2-adrenergic agonists (e.g., formoterol, salmeterol) have a limited role in treating exercise-induced bronchospasm.

Aims Previous bronchoprovocation studies indicate that nifedipine attenuates airway responsiveness to several stimuli whereas diltiazem has no effect. The aim of this study was to determine whether such studies predict the efficacy of calcium channel blockers as maintenance therapy for persistent asthma. Methods Twenty-one otherwise healthy adults with persistent asthma, mean age 25 years, completed treatment with maximum tolerated doses of placebo (P), nifedipine (N), and diltiazem (D) in a double-blind, randomized, three-treatment, three-period, crossover manner, each for 4 weeks. Frequency and severity of asthmatic symptoms were recorded twice daily, as well as peak expiratory flow and frequency of ‘prn’ use of inhaled terbutaline. Blood pressure, heart rate, P-R interval of the ECG and spirometry were measured biweekly. At the end of each treatment, airway responsiveness to exercise was measured. Results The mean (s.e. mean)% of days with wheeze was 69±7% during P, 75±6% during N and 72±6% during D (P=0.7). FEV1 was 79±2% of predicted during P, 81±2% during N and 79±2% during D (P=0.6). The decrease in FEV1 after exercise was 32±4% during P, 32±5% during N and 27±4% during D (P=0.5). Heart rate was elevated during N (P=0.0002) whereas P-R interval was prolonged during D (P=0.0001). Conclusions Maintenance therapy with calcium channel blockers, at doses that produce cardiovascular effects, do not suppress the signs and symptoms of persistent asthma. Previous bronchoprovocation studies did not predict these results.

Background Omalizumab, an anti-IgE monoclonal antibody, is administered by injection once or twice monthly in offices and clinics. It offers a potential alternative intervention for patients with allergic asthma that is not well controlled because of recalcitrant poor adherence to inhaled corticosteroid therapy. Objective To assess the effect of omalizumab therapy by measuring airway responsiveness to adenosine, a marker of allergic airway inflammation, and resource use. Methods Patients (N = 17) aged 6 to 26 years (mean age, 16.4 years) with poorly controlled persistent allergic asthma, less than 50% adherence to inhaled corticosteroid therapy, a forced expiratory volume in 1 second (FEV 1 ) of 60% predicted or higher, and adenosine provocation concentration that caused a decrease in FEV 1 of 20% (PC 20 ) of 60 mg/mL or less were randomized to receive 4 months of omalizumab or placebo in a double-blind, crossover trial with a 3- to 4-month washout between treatments. Patients were instructed to continue taking inhaled corticosteroids throughout the study. The PC 20 was measured before and after each period. Results Fifteen patients completed the study. The mean baseline PC 20 was 14.1 mg/mL (95% CI, 10.8–18.4 mg/mL). The fold change PC 20 was 0.9 (95% CI, 0.5–1.7) during placebo and 3.1 (95% CI, 1.6–6.2) during omalizumab treatment; the estimated ratio was 3.4 (95% CI, 1.2–9.3; P = .02). Six patients required one or more short courses of oral corticosteroids for asthma exacerbations during placebo, but none required this intervention during omalizumab. During the study, the median prescription refills for inhaled corticosteroids was 0.15 (95% CI, 0.00–0.33) canisters per month. Conclusion Omalizumab therapy is an alternative for patients with more severe poorly controlled asthma in whom adherence does not improve with conventional interventions. Trial Registration clinicaltrials.gov Identifier: NCT00133042.

Objective To examine the comparative effectiveness of inhaled long-acting beta-agonist (LABA), inhaled corticosteroid (ICS), and ICS/LABA combinations. Methods We used a retrospective cohort design of patients older than 12 years with asthma diagnosis in the Clinical Practice Research Datalink to evaluate asthma-related morbidity measured by oral corticosteroid (OCS) initiation within 12 months of initiating LABAs, ICSs, or ICSs/LABAs. Asthma severity 12 months before drug initiation (use of OCSs, asthma-related hospital or emergency department visits, and number of short-acting beta-agonist prescriptions) and during follow-up (short-acting beta-agonist prescriptions and total number of asthma drug classes) was adjusted as a time-varying variable via marginal structural models. Results A total of 51,103 patients with asthma were followed for 12 months after receiving first prescription for study drugs from 1993 to 2010. About 92% initiated ICSs, 1% initiated LABAs, and 7% initiated ICSs/LABAs. Compared with ICSs, LABAs were associated with a 10% increased risk of asthma exacerbations requiring short courses of OCSs (hazard ratio [HR] 1.10; 95% confidence interval [CI] 1.07–1.18). ICS/LABA initiators were 62% less likely than ICS initiators (HR 0.38; 95% CI 0.12–0.66) and 50% less likely than LABA initiators to receive OCS prescriptions for asthma exacerbations (HR 0.50; 95% CI 0.14–0.78). Conclusions In concordance with current asthma management guidelines, inhaled LABAs should not be prescribed as monotherapy to patients with asthma. The findings suggest the presence of time-dependent confounding by asthma severity, which was accounted for by the marginal structural model.

Study Objective. To evaluate adherence to oral montelukast and inhaled fluticasone in children with persistent asthma and to determine if age, monotherapy, and duration of therapy affect adherence. Design. Retrospective analysis. Setting. Pediatric pulmonary clinic. Patients. One hundred seventy-one children with asthma who required continuous treatment with a controller agent year-round and in whom montelukast and/or fluticasone had been prescribed for at least 90 days. Intervention. Montelukast monotherapy had been prescribed for 54 patients, fluticasone monotherapy for 48 patients, and combination therapy for 69 patients. Measurements and Main Results. Prescription refill histories were obtained from pharmacies identified by the parents or from Medicaid pharmacy reimbursement records. The maximum possible adherence was calculated as [(no. of doses refilled)/(no. of doses prescribed)] × 100, for a mean observation period of 203 days (range 84–365 days) for montelukast and 314 days (range 97–365 days) for fluticasone. Median adherence rates were 59% (95% confidence interval [CI] 48–65%) for montelukast and 44% (90% CI 35–50%) for fluticasone. Adherence did not significantly correlate with age, length of observation period, or whether the patient was receiving monotherapy or combination therapy. The odds ratio for very poor adherence (< 50%) was 2.0 (95% CI 1.3–3.2) for fluticasone relative to montelukast. Conclusions. Adherence to both drugs was suboptimal. However, these data indicate that our patients were likely to take montelukast more consistently than fluticasone. Whether this translates into better asthma control requires further study.

Poor adherence to medications and other aspects of the treatment plan is common in pediatric patients with asthma, and is a common reason for inadequate asthma control. In selected patients we have used electronic monitoring of pulmonary function, behavior contracts, home nursing visits, and medical neglect reports in an attempt to improve adherence and asthma control. Improved outcomes were seen with the most aggressive intervention, home nursing, and medical neglect referral, but not with less aggressive measures.

Albuterol is a 50:50 mixture of R-albuterol, the active enantiomer, and S-albuterol, which appears to be inactive in humans. The Food and Drug Administration recently approved levalbuterol, the pure R-isomer, as a preservative-free nebulizer solution. Published studies indicate that it is neither safer nor more effective than an equimolar dose of racemic albuterol (levalbuterol 1.25 mg = albuterol 2.5 mg). However, these studies were conducted in patients with stable asthma (at the top of the dose-response curve), whereas a nebulized bronchodilator most likely would be used by patients with an acute exacerbation. Because such patients, in the hospital setting, often require higher doses of albuterol, the manufacturer's recommended dose of levalbuterol is likely to be too low for rescue therapy. Levalbuterol may cost as much as 5 times more than racemic albuterol, depending on purchase method. We conclude that levalbuterol offers no advantage over albuterol but is likely to be more costly.

BACKGROUND: A study was undertaken to determine whether montelukast, a new potent cysteinyl leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction. The relationship between the urinary excretion of LTE4 and exercise-induced bronchoconstriction was also investigated. METHODS: Nineteen non-smoking asthmatic patients with a forced expiratory volume in one second (FEV1) of > or = 65% of the predicted value and a reproducible fall in FEV1 after exercise of at least 20% were enrolled. Subjects received placebo and montelukast 100 mg once daily in the evening or 50 mg twice daily, each for two days, in a three-period, randomised, double blind, crossover design. In the evening, approximately 20-24 hours after the once daily dose or 12 hours after the twice daily dose, a standardised exercise challenge was performed. Data from 14 patients were available for complete analysis. RESULTS: The mean (SD) maximal percentage decrease in FEV1 after exercise was 29.6 (16.0), 17.1 (8.2), and 14.0 (9.4) for placebo, once daily, and twice daily regimens, respectively. The mean (95% CI) percentage protection was 37 (15 to 59) for the group who received 50 mg twice daily and 50 (31 to 69) for those who received 100 mg once daily. Active treatments were not different from each other. The mean (SD) plasma concentrations of montelukast were higher after the twice daily regimen (1.27 (0.81) microgram/ml) than after the once daily regimen (0.12 (0.09) microgram/ml); there was no correlation between the percentage protection against exercise-induced bronchoconstriction and plasma concentrations. After exercise urinary excretion of LTE4 increased significantly during placebo treatment (from 34.3 to 73.7 pg/mg creatinine; p < 0.05) but did not correlate with the extent of exercise-induced bronchoconstriction. CONCLUSIONS: Montelukast protects similarly against exercise-induced bronchoconstriction between plasma concentrations of 0.12 and 1.27 micrograms/ml. The increase in the urinary excretion of LTE4 after exercise and the protection from exercise-induced bronchoconstriction with a cysteinyl leukotriene receptor antagonist provide further evidence of the role of leukotrienes in the pathogenesis of exercise-induced bronchoconstriction.

Background Inhaled racepinephrine (RE) (Asthmanefrin) became available in September 2012 as a nonprescription treatment for bronchospasm based on a 1986 US Food and Drug Administration rule. It contains 11.25 mg RE in 0.5 mL and is delivered by a handheld electronic nebulizer. In 2001, we conducted a pilot study that was never published. Now that the product is promoted as a replacement for epinephrine chlorofluorocarbon metered-dose inhaler (Primatene), we provide the results of that study. Methacholine challenge was used as a bioassay. Objective To determine the dose of RE that is equivalent to nebulized albuterol. Methods Four subjects, 18 to 45 years old, with mild stable asthma completed the pilot study. Methacholine challenge was performed on the first screening day, without pretreatment, and then on different days, 15 minutes after 1.25 mg albuterol and 2.5, 5, 10, and 20 mg RE delivered by a Pari LC Plus nebulizer. The end point was the provocative concentration of methacholine that caused a 20% decrease in FEV 1 . Data were log transformed and analyzed by an ANOVA for repeated measures. Results There was a significant dose response for RE. The geometric mean provocative concentration of methacholine that caused a 20% decrease in FEV 1 was 44 mg/mL (95% CI, 23-85 mg/mL) after albuterol, and 10.2 mg/mL (95% CI, 3.5-30 mg/mL) after the 10-mg dose of RE (approximate nonprescription dose) ( P = .001). There were no adverse effects. Conclusion RE provides less bronchoprotection from methacholine than does albuterol and may be less effective in treating acute bronchospasm.

This was a pilot, randomized, double-blind, crossover, proof-of-concept, clinical endpoint study to examine the hypothesis that exhaled nitric oxide (eNO) in asthmatic subjects can demonstrate bioequivalence of fluticasone propionate in Test and Reference combination products. Subjects had ≥6-month history of asthma and screening eNO was ≥60 parts per billion. eNO was ≥55 parts per billion and forced expiratory volume in 1 second (FEV1) was ≥50% predicted, at start of each treatment period. Subjects presented once each consecutive morning in the clinic during each of three weekly treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 Advair® combination product. Daily eNO was the highest of 3 measurements; one inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washout. One hundred and five subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percent eNO decrease from day 1 baseline at each treatment period was 36.6, 45.3, and 54.6 with combination product 100/50, 250/50, and 500/50, respectively. Tukey multiple comparisons with 10,000 Monte Carlo simulations indicated that with 60 subjects a difference could be detected with ≥80% power between 100/50 and 250/50 (power 97.2%), 250/50 and 500/50 (83.6%), and 100/50 and 500/50 (>99%). Sample sizes to demonstrate bioequivalence of fluticasone propionate Test and Reference, using a crossover design with 6 treatments, for intervals of 0.67 to 1.5 and 0.8 to 1.25 with 80% power are 94 and 216 respectively, using Emax. Thus, this model can establish bioequivalence. This article is protected by copyright. All rights reserved

Background: The purpose of this study was to compare the protection afforded by individualized doses of theophylline and a cromolyn metered-dose inhaler (MDI) during allergen challenge. Methods: The study design was randomized, double-blind, and crossover. Responses to inhaled allergen were measured in 16 subjects with allergic asthma (age range, 18 to 35 years) after 7 days of treatment with either placebo, once daily slow-release theophylline producing a mean ± SD serum concentration of 16 ± 5 μg/ml during the late phase, or 2 mg of cromolyn administered by MDI four times daily. Forced expiratory volume in 1 second was measured at frequent intervals, and airway responsiveness to histamine was measured before and 3 hours after allergen challenge. Results: The mean ± SD maximum decrease in forced expiratory volume in 1 second during the late phase was 30% ± 14% during placebo treatment, 16% ± 13% during theophylline treatment, and 13% ± 14% during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). The geometric mean fold increase in airway responsiveness was 3.0 ± 1.7 during placebo treatment, 1.7 ± 1.7 during theophylline treatment, and 1.5 ± 1.6 during cromolyn treatment (placebo vs theophylline and cromolyn, p = 0.0001; theophylline vs cromolyn, p = 0.1). Conclusions: Theophylline, when administered once daily as a slow-release formulation, was as effective as cromolyn, administered four times daily through an MDI, in attenuating airway responses to inhaled allergen. The protection afforded by both treatments, however, was modest when compared with the results of similar studies with inhaled corticosteroids or other cromolyn formulations that deliver more drug to the lungs than the MDI available in the United States.

Study objective To compare the effectiveness of administration of albuterol by nebulizer or by a metered-dose inhaler having a holding chamber attachment (hereafter "inhaler") for treatment of acute asthma in an emergency department (ED). Design A randomized, double-blind, placebo-controlled intervention study conducted at two sites. Setting The EDs of a large municipal hospital and a university teaching hospital. Patients Thirty-five patients 10 to 45 years of age seeking treatment at an ED for acute asthma. Interventions Patients were randomly assigned to receive either albuterol by nebulizer plus placebo by inhaler (n = 20) or albuterol by inhaler plus placebo by nebulizer (n = 15). The dose was repeated every 30 min until the FEV 1 was at least 80 percent of predicted, the patient became asymptomatic, or 6 doses had been given. Measurements and results All references in this article to spirometric measurements of forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), and peak expiratory flow rate (PEFR) represent percentages of the predicted normal value. No significant (p>0.58) differences occurred in baseline mean FEV 1 , FVC, or PEFR for the two groups. For both groups, significant improvement occurred in mean FEV 1 at 30 min (p 1 (p 0.6) differences occurred between groups in mean FEV 1 , FVC, or PEFR at 30 and 60 min, or in maximum improvement attained. The sample size was sufficiently large to detect a 12 percent difference in improvement with a power of 90 percent. Thirty-three of 35 patients were treated successfully with the study protocol, became asymptomatic, and were discharged home. One patient from each group required further treatment. Conclusions There was no detectable difference in effectiveness of albuterol administered by nebulizer or the inhaler system for treatment of acute asthma. There was no detectable difference in effectiveness of albuterol administered by nebulizer or the inhaler system for the treatment of acute asthma when the dose was titrated to clinical response. When compared with nebulizer, the metered-dose inhaler with holding chamber delivers a full dose of albuterol more quickly and at no higher cost.

Purpose : To determine whether intravenously administered theophylline, when added to frequently nebulized albuterol and intravenously administered methylprednisolone, benefits children hospitalized with severe asthma. Design : Prospective, randomized, placebo-controlled, parallel-group, double-blind study. Setting : Inpatient pediatric service at a tertiary-care teaching hospital. Patients : Twenty-one children 5 to 18 years of age. Interventions : All patients received 2.5 to 5.0 mg of nebulized albuterol every 20 minutes to every 6 hours, intravenously administered methylprednisolone (1 mg/kg every 6 hours), and either intravenously administered theophylline (as aminophylline) or placebo for 36 hours. Serum theophylline concentrations were maintained between 55 and 110 μ mol/L (between 10 and 20 μ g/ml) by adjusting loading doses and continuous infusion rates. Measurements and main results : Forced expired volume in 1 second (FEV 1 ) and clinical score were measured at 0, 1, 3, 6, 12, 24, and 36 hours after the start of each individual study. The total number of nebulizations, total albuterol dosage, adverse effects, and duration of hospital stay were recorded. Twelve children received theophylline and nine recelved placebo. The two group did not differ significantly in age, sex, or baseline FEV 1 . In both groups, clinical score significantly improved from baseline by 12 hours, and FEV 1 by 24 hours ( p 1 or clinical score at any of the measured time points. There were no significant differences in rate of improvement in FEV 1 , total number of nebulizations, total albuterol dosage, or duration of hospital stay. Adverse effects were mild and infrequent and did not differ significantly between the two groups. Conclusions : Theophylline, at therapeutic concentrations, did not additionally benetit children hospitalized with severe asthma who were being treated frequently with nebulized albuterol and with methylprednisolone intravenously.

Measurement of fractional exhaled nitric oxide (FENO) is recommended as an adjunct in the diagnosis of eosinophilic airway inflammation, to determine the likelihood of corticosteroid responsiveness, to monitor therapy, and to assess adherence to inhaled corticosteroid therapy. The American Thoracic Society Guidelines for the interpretation of FENO concentrations identify cut points in children of greater than 35 parts per billion (ppb) for eosinophilic airway inflammation and less than 20 ppb for no inflammation. For adults, the guidelines recommend greater than 50 ppb and less than 25 ppb, respectively. The NIOX MINO (Aerocrine AB, Solna, Sweden) is a commonly used portable method of analyzing FENO that does not require calibration. The accuracy and precision of this device were largely determined by extensive in vitro testing for US Food and Drug Administration clearance. The same is true for its successor, the NIOX VERO. The clinical study in the MINO FDA submission was a single measurement before and after beginning inhaled corticosteroids, which demonstrated a decrease in FENO. Other published clinical studies are single visit comparisons with other methods or multiple technicians. Only one study compared 2 measurements on different days. Because there are no published reports on the long-term reproducibility of devices used to measure FENO, we undertook the following study. We analyzed 451 quality control measurements obtained over a 2-year period from 5 devices. There were 5 nonasthmatic technicians (quality control subjects) who performed these measurements on each day that the device was used for a clinical study or patient care (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org for more details). All control subjects met the manufacturer’s criteria, which included >18 years old, no ongoing cold or known airway disorder, nonsmoker, expected stable exhaled nitric oxide values between 5 and 40 ppb during the qualification period, and preferably no allergies (except seasonal) or asthma. To obtain a control FENO measurement, each technician was required to empty his or her lungs by slowly exhaling and then forming a tight seal around the mouthpiece, making sure not to let the air leak out. Then, they inhaled to total lung capacity and exhaled forcefully for approximately 10 seconds through the mouthpiece while responding to sound and light cues on the LCD to guide the rate of exhalation. The general linear model procedure was used to determine whether there was a device*subject interaction. Because the interaction was significant (P .05). Measurements for subjects 3-5 who used device 5 were 31.79 (7.2), 11.51 (4.2), and 15.0 (4.1) ppb, respectively (Figure 2). Measurements for subject 3 were significantly higher than those for subjects 4 and 5 (P < .0001). Eighty-two percent of her values were above 25 ppb. The NIOX MINO portable device employing an electrochemical methodology was cleared by FDA as “substantially equivalent” to the chemiluminescence stationary method (NIOX), largely based on extensive in vitro testing using certified nitric oxide in nitrogen calibration gas. Similarly, the new NIOX VERO was cleared in the same way as “substantially

Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis.We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored.There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% +/- 24.9% and 17.8% +/- 13.6%, respectively, whereas the mean stool weight decreased by 517 +/- 362 g.TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.

Background Many health care professionals believe that a nonprescription epinephrine metered-dose inhaler is less effective and shorter acting and has more cardiovascular adverse effects than prescription β 2 -agonists. Objective To determine if increasing the epinephrine dose improves efficacy safely. Methods Eight patients with nocturnal asthma (age range, 20-46 years) were treated in a randomized, crossover manner on 2 different nights while sleeping in a clinical research center. On awakening from asthma symptoms, 2, 4, and 8 actuations of epinephrine or albuterol were administered at 17-minute intervals (14 cumulative actuations). Forced expiratory volume in 1 second (FEV 1 ), asthma symptoms, and systemic effects were measured before the first dose, during the 9- to 17-minute period after each dose, and 30 minutes after the last dose. Results The mean ± SD FEV 1 at the onset of symptoms was 45% ± 11% and 44% ± 12% predicted before epinephrine and albuterol, respectively, and increased to a maximum of 86% ± 11% and 93% ± 10%, respectively ( P = .04). Symptoms decreased as FEV 1 improved and did not return after either treatment; 6 patients were symptom free after 14 cumulative actuations of epinephrine compared with 6 cumulative actuations of albuterol. Heart rate decreased to 71 ± 10/min after epinephrine but increased to 92 ± 14/min after albuterol ( P = .001). After the last dose, serum potassium concentration was 3.6 ± 0.3 μmol/L after epinephrine and 3.2 ± 0.4 μmol/L after albuterol ( P = .01). Conclusion Epinephrine was nearly as effective as albuterol in terminating an acute episode of airway obstruction but without cardiovascular effects in these otherwise healthy young adults.

Th2 cytokines play an important role in producing and maintaining airway inflammation in asthma. As a consequence, there is considerable interest in developing agents that modulate their effects. Therapeutic strategies include decreasing cytokine synthesis or release, blocking their effects by antibodies or soluble receptors, as well as administration of anti-inflammatory cytokines. Initial studies of three of these approaches have shown interesting results. The first is suplatast tosilate, a selective Th2-inhibitor that suppresses the synthesis of IL-4 and IL-5 in vitro. In a randomised double-blind placebo-controlled parallel study, suplatast, given orally TID, improved lung function and symptom control when added to inhaled beclomethasone for 4 weeks and prevented deterioration when the beclomethasone dose was decreased by 50% during a second 4 weeks. The second is CDP840, a second generation phosphodiesterase type 4 inhibitor, that may decrease the release of cytokines from eosinophils and Th2 lymphocytes. In a double-blind placebo-controlled crossover study, CDP840, given orally BID for 9 days, attenuated the late response to allergen by 30% when compared to placebo. The third is a recombinant human soluble IL-4 receptor (altrakincept) that neutralises endogenously produced IL-4. In inhaled steroid-dependent subjects, weekly nebulisation of altrakincept prevented lung function decline and asthma exacerbations after abrupt withdrawal of inhaled corticosteroids. In contrast, studies of anti-IL-5 monoclonal antibodies (mepolizumab and SCH55700) indicate that this strategy only partially depletes eosinophils from the bronchial mucosa and shows no benefit on clinical markers of asthma activity. Of these novel therapeutic approaches, inhibiting Th2 synthesis of IL-4 and IL-5 (suplatast) appears to offer the greatest potential and long-term studies of this approach should be undertaken.

If started early and at high doses, the acute use of inhaled corticosteroids (ICS) provides modest benefit in patients with mild exacerbations of asthma. In more severe exacerbations, oral corticosteroids are significantly more effective in preventing hospitalizations and improving lung function. We conclude that ICS should not be used routinely to treat acute exacerbations. (J Pediatr 2003;142:S26-S33)

Oral corticosteroids are as effective as intravenous therapy for treating acute exacerbations of asthma. They are available in tablets that can be crushed and mixed with soft food or syrup, and in a variety of liquid formulations that differ in volume required, palatability, patient acceptance, and cost. The most important consideration in product selection for a young child is that the doses can be easily swallowed and retained.

Study Objective. To determine if differences between holding chambers in previous in vitro aerosol studies would agree with the bioavailability of inhaled fluticasone propionate between the same holding chambers in children with asthma. Design. Double-blind, randomized, crossover study. Setting. University of Florida Clinical Research Center. Patients. Eight children (aged 5–9 yrs) with stable asthma. Intervention. Under observation, the children inhaled two 110-μg puffs of fluticasone twice/day through the InspirEase or E-Z Spacer holding chamber. Measurements and Main Results. Blood samples were collected at baseline and then at 0.5, 1, 1.5, 2, 4, and 6 hours after the last dose of fluticasone. Primary outcome measures were peak fluticasone steady-state plasma concentration (Cmax) and area under the fluticasone plasma concentration-time curve from 0–6 hours (AUC0–6). The fluticasone plasma concentrations were determined by high-performance liquid chromatography-mass spectrometric assay. Mean ± SD Cmax from InspirEase (245 ± 77 pg/ml) was 18% higher than that after E-Z Spacer (199 ± 58 pg/ml, p

Objective: To determine whether a prescription refill history obtained by telephoning patients' pharmacies identifies poor adherence with asthma medications more frequently than physician assessment. Methods: The study population consisted of 116 children with persistent asthma who were Medicaid recipients; patients who received medication samples were excluded. During a clinic visit pulmonologists interviewed patients, caretakers, or both and estimated adherence on a checklist. A nurse asked the caretakers where they obtained medications and telephoned 66 identified pharmacies for refill histories. The maximum possible adherence was calculated as the number of doses refilled/number of doses prescribed × 100 for a mean duration of 163 days (range, 63 to 365 days). The accuracy of the refill information was determined from Medicaid reimbursement records. Results: Information provided by pharmacies was 92% accurate. The mean (95% CI) of maximum potential adherence was 72% (65%,77%) for theophylline, 61% (55%,68%) for inhaled corticosteroids, and 38% (23%,53%) for cromolyn; only cromolyn and theophylline were significantly different. Physicians were able to identify 21 (49%) of 43 patients who refilled ≤50% of prescribed doses of long-term symptom controllers and only 3 (27%) of 11 patients who used albuterol excessively. Conclusions: Physicians often were unable to identify patients with very poor adherence. Checking prescription refills is an accurate and practical method of identifying such patients. (J Pediatr 2000;136:532-6)

Background: Some nebulized bronchodilator solutions contain additives, such as EDTA, benzalkonium chloride (BAC), or both. Objective: Although BAC-induced bronchoconstriction has been well documented in patients with asthma, there is no information on the effects of EDTA on FEV 1 when inhaled in the amounts that would be administered during emergency department treatment of asthma. Methods: Eighteen subjects with stable asthma and airway responsiveness to methacholine were randomly assigned to inhale up to four 600-μg nebulized doses of EDTA, BAC (positive control), and normal saline (placebo) in a double-blind crossover manner on separate days. FEV 1 was measured 15 minutes after each dose. Treatments were repeated every 20 minutes until FEV 1 decreased by 20% or greater or a maximum of 4 doses were administered. Results: Mean ± SD maximum percent decrease in FEV 1 was 1.8% ± 5.8% after EDTA, 16.6% ± 13.9% after BAC, and 3.6% ± 8.2% after placebo ( P Conclusion: The amount of EDTA contained in maximum recommended doses of nebulized bronchodilators does not induce bronchospasm. In contrast, BAC induces clinically important bronchospasm, which could decrease the efficacy of a bronchodilator during an emergency. (J Allergy Clin Immunol 2001;107:68-72.)

Study objective To evaluate the effect of a potent experimental leukotriene receptor antagonist, MK-571, on airway responses to inhaled allergen. Design Randomized, double-blind, placebo-controlled, crossover trial. Setting Clinical research center. Subjects Eight male volunteers with allergic asthma. Interventions An intravenous loading dose was followed by an 8-hour infusion of MK-571 or placebo, with a 7- to 14-day washout between treatments. Allergen challenge was performed after the loading dose and a histamine challenge was performed before and 24 hours after allergen. Measurements and main results Forced expiratory volume in 1 second was measured serially. MK-571 provided about 50% protection during maximum early and late responses compared with placebo (p=0.005), but airway obstruction persisted 8-24 hours after allergen on both treatment days. Airway responsiveness to histamine was not significantly attenuated at 24 hours. Conclusion Blocking Cys LT1 receptors for 8 hours attenuated the early and late responses but did not interrupt the cascade of events leading to subsequent allergen-induced airway obstruction and hyperreactivity.

Because chlorofluorocarbons (CFCs) contribute to depletion of stratospheric ozone, CFC-containing metered-dose inhalers (MDIs) such as Ventolin and Proventil are being phased out of production. In terms of delivery of albuterol to the lungs, we compared an alternative delivery system, the Spiros dry-powder inhaler (DPI), with Ventolin, using a methacholine challenge-based clinical bioassay. Twenty-four adults and adolescents with asthma completed this double-blind, four-period crossover study. Doses evaluated were one and three actuations each of Spiros and Ventolin (90- and 270-microgram albuterol base). A methacholine challenge (Cockcroft method) was initiated 3 h before and 0.25 h after albuterol. Predose PC(20)FEV(1) values were not significantly different between study days. Postdose PC(20)FEV(1) results met standard bioassay study validity criteria: i.e., a significant dose-response relationship was present (p = 0.0002); tests for deviation from parallelism and overlap of dose-response curves were nonsignificant (p = 0.08, 0.69). By using Finney 2-by-2 bioassay analysis, we estimate that each Spiros actuation delivers 1.12 times as much albuterol to the airways as one Ventolin actuation (90% confidence interval, 0.68 to 1.94). There were no significant differences in markers of systemic effects (vital signs, potassium, and blood glucose concentrations). We conclude that Spiros and Ventolin inhalers deliver comparable quantities of albuterol to the airways.

Background Having observed in recent years that the theophylline dose requirements needed to attain peak serum concentrations of 10 to 20 μg/ml infrequently reached previously described mean values, we hypothesized that a downward shift in the range of dose requirements had occurred among patients with asthma. Study design We examined dosage requirements needed to attain peak serum concentrations of 10 to 20 μg/ml in all patients with chronic asthma treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared these doses to previous dose requirements from 1978 to 1983 determined in the same manner. Results Despite similar mean peak serum concentrations during both time periods (14 μg/ml), mean theophylline dosage requirements during the period of this study were approximately 25% lower among all age groups than those previously observed (p < 0.001). There were no significant differences in mean dosage requirements between the Iowa and Florida patients in any age group examined. Conclusions Theophylline dose requirements needed to attain serum concentrations of 10 to 20 μg/ml have decreased significantly from those on which current dosing recommendations are based. This suggests a decrease in mean clearance of the population. Clinical Pharmacology & Therapeutics (1997) 62, 483–489; doi

Theophylline has been a popular medication for asthma for over 50 years. However, the introduction of newer pharmacologic agents, concern about the toxicity of theophylline, and recommendations in widely disseminated guidelines have recently contributed to its decreased use. In this review we reassess the role of theophylline in the pharmacotherapy of asthma and specifically address three pivotal questions: What are the data justifying its continued use? What are its risks? What is its role in the treatment of patients with asthma? History Although first used as intravenous therapy for acute asthma1 and then as an oral medication in fixed doses . . .

Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.

Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5, 10, 20, 40, 80, and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect, the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil, compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly, bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge, 13 subjects inhaled placebo, 10 mg, or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo, -12.7 +/- 4.3 percent after 10 mg (p less than 0.05), and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but, paradoxically, induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect, high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.