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Ineffective over-the-counter (OTC) drugs should be removed from the US market. Despite solid research showing that oral phenylephrine is ineffective as a decongestant, the US Food and Drug Administration has failed to respond to a 2015 citizen’s petition to remove it from the OTC nasal decongestant monograph. Other examples of scientifically proven ineffective OTC medications include guaifenesin as an expectorant, dextromethorphan as a cough suppressant, and chlorpheniramine for cold symptoms.

The surge in COVID-19 cases during the 2020 Spring led to a nationwide shortage of albuterol inhalers. As a new surge has begun, shortages may make it difficult for patients with obstructive lung disease, including children with asthma, to obtain refills. Since there is no evidence that albuterol relieves symptoms in COVID-19 patients with respiratory symptoms not caused by bronchospasm, it is reasonable for clinicians to not prescribe it for COVID-19 patients unless they also have asthma or chronic obstructive pulmonary disease.

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.

Objectives Little is known about emergency medical services' (EMS') management of pediatric asthma. This study's objective was to describe the demographic, clinical, and geographic characteristics of current EMS' management of pediatric asthma in the state with the fourth-largest pediatric population. Methods This was a retrospective observational study of EMS patients ages 2 to 18 years with an asthma exacerbation from 2011 to 2016. Patients from Florida's EMS Tracking and Reporting System were included if their EMS chief complaint indicated respiratory distress, if they received at least 1 albuterol treatment, and if they were transported to a hospital. Results A total of 11,226 patients met the inclusion criteria. The median age was 9 years, and 49% were African-American. Geospatial analysis revealed 4 rural counties with disproportionate numbers of African-American patients. In addition to albuterol, 37% of patients received ipratropium bromide and 9% received systemic corticosteroids. Adjusted logistic regression revealed that the strongest predictors of receiving systemic corticosteroids from EMS were intravenous access (odds ratio, 33.4; 95% confidence interval, 24.4-45.6) and intravenous magnesium sulfate administration (odds ratio, 5.0; 95% confidence interval, 3.4-7.3), indicating a more severe presentation. Conclusions This statewide study demonstrated low rates of EMS administration of ipratropium bromide and systemic corticosteroids, both evidence-based treatments for asthma exacerbations. Targeted EMS education should attempt to increase utilization of both those medications. In addition, the feasibility and efficacy of EMS administration of oral systemic corticosteroids for children should be explored.

Background Pediatric asthma exacerbations are a frequent reason for emergency care. Early administration of oral systemic corticosteroids (OCS) in the emergency department (ED) decreases hospitalization rates and ED length-of-stay (LOS). However, it is unknown whether even earlier OCS administration by emergency medical services (EMS) in the prehospital setting further improves outcomes. Purpose To describe the background and methods of a type 1 hybrid effectiveness-implementation trial of EMS-administered OCS for pediatric asthma patients incorporating a stepped wedge design and the RE-AIM framework. Methods The study employs a non-randomized stepped wedge design where multiple EMS agencies adopt OCS as a treatment for pediatric asthma exacerbations at varying times. This design accommodates ethical considerations of studying pediatric subjects in the prehospital setting where informed consent is not feasible. We will compare hospitalization rates, ED LOS, and short-term healthcare costs between pediatric asthma patients who do and do not receive OCS from EMS. Using geographic information systems (GIS), we will measure how differences in outcomes scale with increasing EMS transport time. We will use the RE-AIM framework to guide a mixed methods analysis of barriers and enablers to EMS administration of OCS for pediatric asthma patients, including quantitative measures of adoption and uptake and qualitative EMS provider focus group data. Conclusion This trial will determine if earlier EMS administration of OCS to pediatric asthma patients decreases hospitalizations, ED LOS, and short-term healthcare costs, and if those outcomes scale with longer EMS transport times. We will identify barriers and enablers to implementing EMS-administered OCS for pediatric asthma patients.

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: Decreasing electrostatic charge on valved holding chambers increases the amount of drug delivered. However, there are no data demonstrating that this increases bronchodilatation. OBJECTIVE: To investigate the influence of reducing electrostatic charge on the bronchodilator response to albuterol inhaler during nocturnal bronchospasm. METHODS: This randomized double-blind, double-dummy crossover study included subjects, 18–40 years old, with nocturnal bronchospasm (20% overnight decrease in peak flow on 3 of 7 nights during run-in), FEV1 60–80% predicted during the day, and ≥ 12% increase after albuterol. Subjects slept in the clinical research center up to 3 nights for each treatment. FEV1 and heart rate were measured upon awakening spontaneously or at 4:00 am, and 15 min after each dose of 1, 2, and 4 cumulative puffs of albuterol via metered-dose inhaler. The drug was administered through an anti-static valved holding chamber (AeroChamber Plus Z-Stat) or a conventional valved holding chamber containing a static charge (AeroChamber Plus). RESULTS: Of 88 consented subjects, 11 were randomized and 7 completed the study. Most exclusions were due to lack of objective evidence of nocturnal bronchospasm. Upon awakening, FEV1 was 44 ± 9% of predicted before the anti-static chamber and 48 ± 7% of predicted before the static chamber. The mean ± SD percent increase in FEV1 after 1, 2, and 4 cumulative puffs using the anti-static versus the static chamber, respectively, were 52 ± 26% versus 30 ± 19%, 73 ± 28% versus 48 ± 26%, and 90 ± 34% versus 64 ± 35%. The point estimates for the differences (and 95% CIs) between the devices (anti-static vs static) were 21% (4–38%) (P = .03), 23% (6–41%) (P = .02), and 25% (7–42%) (P = .01) for 1, 2, and 4 cumulative puffs, respectively. There was no significant difference in heart rate between treatments. CONCLUSIONS: Delivery of albuterol through an anti-static chamber provides a clinically relevant improvement in bronchodilator response during acute, reversible bronchospasm such as nocturnal bronchospasm.

We determined lung bioavailability of a fluticasone propionate (FP) pressurised metred-dose inhaler (Flovent HFA; GlaxoSmithKline, Research Triangle Park, NC, USA) administered via AeroChamber Plus (Monaghan Medical, Plattsburgh, NY, USA) with Facemask and Babyhaler (GlaxoSmithKline) valved holding chambers (VHCs) using a population pharmacokinetic approach. Children from 1 to

Inhaled long-acting β2-adrenergic agonists (LABAs) are recommended in the treatment of asthma as maintenance therapy when combined with an inhaled corticosteroid or when used alone to prevent exercise-induced bronchospasm.1 In addition, they are recommended alone or in combination with a long-acting inhaled anti-cholinergic or an inhaled corticosteroid as maintenance therapy for chronic obstructive pulmonary disease.2 Formoterol, salmeterol, and arformoterol are the only LABAs currently available in the United States, and they are marketed in various formulations alone or in combination with an inhaled corticosteroid. Although patents are still in force for several drug products containing a LABA (i.e., drug and device), the patents on the drug substance (i.e., the drug alone) have expired. Therefore, pharmaceutical firms have developed or are interested in developing alternative delivery devices for two of these drugs, and in some cases attempts are being made to develop a generic version. Obtaining U.S. Food and Drug Administration (FDA) approval of a generic LABA includes a requirement for an in vivo dose-response study to establish bioequivalence,3 and under varying circumstances, such a study is required by the European Medicines Agency4 and Canada’s Human Protection Branch.5 The purpose of such a study is to determine whether a test and reference product meet equivalence criteria based on a bioassay sensitive to differences in dose. If the study design is not sufficiently sensitive to detect a difference in two doses of the reference product, then it would not be possible to detect a difference between the test and reference products in the amount of drug delivered to the airways.6 In the United States, pharmacokinetic studies are not sufficient, by themselves, to establish a dose-response relationship,3 since plasma concentrations have not been proven to indicate where in the airways the drug is delivered and do not distinguish drug absorbed from the lungs and drug absorbed from the swallowed portion of the dose in the gastrointestinal tract.7 Thus, a pharmacodynamic end point is required to demonstrate the amount of drug delivered to the relevant receptors in the airways.8 Conventional bronchodilator studies, where the forced expiratory volume in 1 second (FEV1) is measured after a dose over time, have been used, but often the dose-response curve with this pharmacodynamic end point is relatively flat.9, 10 That is, during typical daytime studies in patients with stable asthma, one actuation may produce the same improvement in FEV1 as two actuations, since the response lies on the upper plateau portion of the dose-response curve.10 Dose-response studies of albuterol have demonstrated that bronchoprovocation with histamine or methacholine are the most sensitive methods of determining differences in doses when delivered by generic and brand chlorofluorocarbon (CFC) metered-dose inhalers (MDIs),11 between a CFC MDI and dry powder inhaler (DPI),12 and between CFC and hydrofluoroalkane (HFA) MDIs.13 Bronchoprovocation with methacholine has been used to compare the intensity and/or duration of formoterol delivered by a DPI or MDI.14–16 However, none of these studies has provided sufficient information to determine whether methacholine challenge can detect a 2-fold or smaller difference in dose and, thus, be useful as a bioassay to determine bioequivalence. Also, they do not provide information on the sample size required for a bioequivalence study. Since the Aerolizer (Foradil Aerolizer; Schering Corp., Kenilworth, NJ) is the only DPI formulation of formoterol available in the United States, it will serve as the reference product for subsequent studies of new delivery devices or generic formulations of this drug. Thus, the purpose of this study was to determine whether a methacholine-based clinical bioassay can be used to evaluate bioequivalence of formoterol (Aerolizer) and other formoterol-containing formulations. This would require that a highly significant dose-response relationship be present, which, in turn, requires a sufficiently steep dose-response slope relative to the response variability observed in the study. In addition, we propose possible improvements in study design that may further increase the statistical power of these bioequivalence methods.

A recent Food and Drug Administration regulation has resulted in the availability of 3 new standardized pancreatic enzyme products with proven short-term efficacy and safety (Creon®, Pancreaze®, and Zenpep®). They comply with modern chemistry, manufacturing, and control criteria, including predictable amounts of enzyme content. However, they differ in available strengths, are not designated by Food and Drug Administration as therapeutically equivalent, and are not interchangeable by pharmacists without previous approval of the prescriber.

Three discussion papers raise interesting points, but at the end of the day, we continue to recommend that past meta-analyses which have influenced public policy or clinical paradigms be reanalyzed by unweighted methods. For all future meta-analyses that employ either (a) fixed effects where concomitant treatment and/or eligibility are diverse or (b) classical random effects weighted methods, unweighted methods should serve as the primary analysis. Other analyses would be reasonable as secondary approaches. Two commentaries suggest that weights are only random to the extent of estimation errors in the between study and within study variance components. We shall demonstrate that even if these components are known, there is still considerable random variability in the weights. In fact, methods that try to weight the estimates inversely proportional to the variance have a number of undesirable properties, including bias, incorrect standard errors, inconsistency (including coverage of confidence intervals), and counter-intuitive properties that the expectation of the estimator changes both with the number of studies sampled and with constant multiples of sample size across all studies. These adverse properties do not exist for the unweighted approach. From the numerical example of phenylephrine 10 mg, despite the arguments of Waksman, the proper conclusion is that the collection of studies does not constitute evidence-based support for efficacy in terms of lowering nasal airway resistance. In the final section, we present two compelling examples where questionable inferences were made, with potential major public implications. Copyright © 2010 John Wiley & Sons, Ltd.

This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.

Background: Oral phenylephrine is used as a decongestant, yet there has been no previously published systematic review supporting its efficacy and safety. Objective: To assess the efficacy and safety of oral phenylephrine as a nonprescription decongestant. Methods: MEDLINE, the Cochrane Central Registry of Controlled Trials, EMBASE International Pharmaceutical Abstracts, and the Federal Register were searched for-English and non–English-language studies published through January 2007 that measured the effects of oral phenylephrine on nasal airway resistance (NAR) in patients with nasal congestion. The retrieved studies were supplemented with information from our personal files and by hand searches of the references in any of the studies. Additionally, a Web of Science Search was conducted using the Cited Reference function for all published clinical trials identified. Studies included in the analysis were randomized, placebo-controlled trials; studies of combination products were excluded. Two investigators independently extracted data on NAR, self-reported decongestant effects, and cardiovascular effects (ie, heart rate, blood pressure) from each of the included studies. Meta-analyses were performed for NAR and cardiovascular effects using a random effects model. Subjective decongestant effects were summarized. Results: Based on 8 unpublished studies that included 138 patients, phenylephrine 10 mg did not affect NAR more than placebo; the mean maximal difference in relative change from baseline between phenylephrine and placebo was 10.1% (95% CI −3.8% to 23.9%). Eight unpublished studies on phenylephrine 25 mg showed a significant reduction of maximal NAR compared with placebo of 27.6% (95% CI 17.5% to 37.7%). There was significant heterogeneity among the studies included in this analysis, which was partially attributable to different laboratories and methods used. Patient-re ported decongestion was not consistently better for any phenylephrine dose compared with placebo, and NAR was a more sensitive measurement of efficacy. Phenylephrine showed no consistent effect on heart rate or blood pressure for doses of 25 mg or less. Conclusions: There is insufficient evidence that oral phenylephrine is effective for nonprescription use as a decongestant. The Food and Drug Administration should require additional studies to show the safety and efficacy of phenylephrine.

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.

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).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 (PC40 R5 ) was calculated.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) PC40 R5 (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.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. 2016;51:570-575. © 2015 Wiley Periodicals, Inc.

The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden.

In the session on “Pharmacodynamic studies to demonstrate efficacy and safety”, presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration–time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of β-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.

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.

Methacholine solutions0.25 mg/mL must be prepared fresh daily, while concentrationsor = 0.25 mg/mL must be prepared at 2-week intervals according to US Food and Drug Administration-required labeling. The purpose of this report was to determine whether freezing methacholine solutions in unit-dose syringes would allow less frequent preparation.Diluent containing 0.5% sodium chloride, 0.275% sodium bicarbonate, and 0.4% phenol was used to prepare 11 concentrations of methacholine ranging from 0.031 to 32.0 mg/mL. Three milliliters of each dilution was placed into 5-mL polypropylene syringes and immediately frozen. Methacholine concentrations were determined using a validated high-performance liquid chromatography assay after preparation (time zero) and at 0.5, 1, 1.5, 2, 3, 4, 5, and 6 months. On the day of analysis, the samples were allowed to thaw to room temperature. An additional set of each dilution was stored at room temperature for 24 h after thawing and then analyzed for methacholine.Samplesor = 0.062 mg/mL analyzed immediately after thawing retainedor = 90% of labeled potency for at least 6 months, while the 0.031-mg/mL sample retained 90% potency for 4 months. Most samples analyzed 24 h after thawing lost potency.If prepared and stored in unit-dose syringes frozen, methacholine solutions containing 0.062 to 32.0 mg/mL can be prepared at 6-month intervals, and solutions containing 0.031 mg/mL can be prepared at 4-month intervals. Once thawed, unused methacholine solutions should be discarded.

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 Prior studies indicate that some devices used to monitor metered-dose inhaler (MDI) use are not accurate. Objective To assess the accuracy of the Doser CT (NEW-MED Corporation; Waltham, MA), the MDILog (Medtrac Technologies; Lakewood, CO), and the SmartMist (Aradigm Corporation; Hayward, CA) in a bench-top study. Design One, two, and four puffs of fluticasone propionate MDI (Flovent; GlaxoWellcome; Research Triangle Park, NC) were actuated twice daily for 30 days with two units of each device. The date and time of each actuation were recorded in a log and then compared with the output of the device. The percentage of doses recorded accurately was compared by analysis of variance. Measurements and results The SmartMist was 100% accurate, while both the Doser CT and MDILog devices occasionally recorded spurious actuations. The Doser CT also had missed actuations after the counter had prematurely reached zero secondary to the spurious recordings. The accuracy (mean ± SD) was 94.3 ± 2.9% for the Doser CT and 90.1 ± 6.9% for the MDILog (p = 0.21). The dose regimen actuated and duration of use did not significantly affect accuracy. Conclusion All three devices are sufficiently accurate to monitor adherence in most clinical settings.

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.

Study objectives To determine optimal storage conditions for histamine diphosphate (HDP) solutions used for bronchoprovocation. Design HDP was dissolved in buffered saline solution to concentrations of 0.125 to 16 mg/mL and stored in 3-mL unit dose syringes at different temperatures for varying lengths of time, with and without protection from fluorescent light. Setting Dark freezer (−20°C), dark refrigerator (4°C), and laboratory counter top (20°C) illuminated by fluorescent light (375 foot-candles). Measurements HDP concentrations were measured after the solutions were prepared and during storage by a high-performance liquid chromatographic assay that differentiates histamine from its break down products. Results All dilutions were sterile after preparation and contained 97 to 110% of the labeled amount of HDP. Solutions constantly exposed to fluorescent light (375 foot-candles) and room temperature (20°C) contained only 20 to 37% of the initial concentrations after 7 days. The same dilutions stored at room temperature, but protected from light, contained 83 to 94% of the initial concentrations. Dilutions stored in the dark in a refrigerator (4°C) retained 97% of the initial concentrations after 8 weeks, while dilutions stored in the dark freezer (−20°C) were stable for 12 months. Conclusions Exposure to fluorescent light at room temperature results in degradation of histamine solutions used for bronchoprovocation. Dilutions stored in unit dose syringes and protected from light are stable for at least 8 weeks in the refrigerator and up to 12 months frozen. Once removed from the refrigerator or freezer, the solutions should be used within 6 h or discarded.

The category of over-the counter (OTC) [nonprescription] drugs was established in the United States in 1951 by the Durham-Humphrey Amendment to the Food, Drug, and Cosmetic Act. The Kefauver-Harris Amendments to the Act required proof of efficacy for all drugs (prescription and nonprescription) approved after 1938. OTC drugs are marketed under regulations that established a monograph approval process, as well as the New Drug Application process. During the 1970s, the US Food and Drug Administration (FDA) convened panels of experts to review the efficacy and safety of OTC products on the market. The panel on Cough, Cold and Allergy Products determined that phenylephrine (PE) and pseudoephedrine were safe and effective for treating nasal congestion. A final OTC Nasal Decongestant Drugs Products monograph was published in 1994. Manufacturers can market the drugs listed in the monograph, alone or in combination, as long as the ingredients, dosage, and instructions for use list exactly what is required in the monograph. Even though phenylpropanolamine was effective, it was not included in the final monograph because of safety concerns about hemorrhagic strokes primarily when used as an OTC appetite suppressant. Because of the widespread use of pseudoephedrine to illegally make methamphetamine, Congress attached an amendment to the Patriot Act, the Combat Methamphetamine Epidemic Act, placing it “behind the counter” and requiring a photo identification and log of the transaction. This removed pseudoephedrine-containing products (Sudafed and others) from grocery and convenience stores, as well as from “in front of the counter” in pharmacies. The use of PE increased dramatically after 2004, presumably because it was the only “in front of the counter” OTC option. In 2005, we reviewed the existing evidence and questioned whether PE was effective at the FDA-approved dose of 10 mg. Subsequently, we undertook a meta-analysis

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: The Medtrac MDI Chronolog is an electronic device for monitoring adherence to metered-dose inhalers. It replaces previous models of the Nebulizer Chronolog and uses a different mechanism of recording actuations. Objective: This study was carried out to determine whether the new model can accurately record and report the date, time, and number of metered-dose inhaler actuations. Methods: Four canisters of beclomethasone (Beclovent) were discharged through four Chronologs with fresh batteries at a rate of 1, 2, 4, or 8 times twice daily for 7 days. Four additional canisters were used as controls and discharged simultaneously through the standard actuator. The weight of all canisters and Chronolog battery voltage were measured before and at the end of the 7-day experiment. The data retrieved from the Chronologs were compared with the information recorded manually during each discharge. Results: The loss in canister weight was consistent for the number of puffs discharged from all four Chronolog units and controls. However, the accuracy of the Chronologs in recording the number of actuations varied between 50% and 100%. The largest amount of data loss occurred with the unit used to discharge 8 puffs and was associated with a dead battery at the end of the 7-day trial. For actuations that were retrievable, the Chronologs accurately recorded the date and time. Conclusions: Unexpected battery voltage drain and other mechanical problems that we encountered may cause data loss and the false appearance of missed doses. Thus the units that we tested were not sufficiently reliable to monitor patient adherence. (J Allergy Clin Immunol 1997;100:488-91.)

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.