Kathryn Blake

Lansoprazole for children with poorly controlled asthma: a randomized controlled trial.

CONTEXT Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. Untreated GER has been postulated to be a cause of inadequate asthma control in children despite inhaled corticosteroid treatment, but it is not known whether treatment with proton pump inhibitors improves asthma control. OBJECTIVE To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER. DESIGN, SETTING, AND PARTICIPANTS The Study of Acid Reflux in Children With Asthma, a randomized, masked, placebo-controlled, parallel clinical trial that compared lansoprazole with placebo in children with poor asthma control who were receiving inhaled corticosteroid treatment. Three hundred six participants enrolled from April 2007 to September 2010 at 19 US academic clinical centers were followed up for 24 weeks. A subgroup had an esophageal pH study before randomization. INTERVENTION Participating children were randomly assigned to receive either lansoprazole, 15 mg/d if weighing less than 30 kg or 30 mg/d if weighing 30 kg or more (n = 149), or placebo (n = 157). MAIN OUTCOME MEASURES The primary outcome measure was change in Asthma Control Questionnaire (ACQ) score (range, 0-6; a 0.5-unit change is considered clinically meaningful). Secondary outcome measures included lung function measures, asthma-related quality of life, and episodes of poor asthma control. RESULTS The mean age was 11 years (SD, 3 years). The mean difference in change (lansoprazole minus placebo) in the ACQ score was 0.2 units (95% CI, 0.0-0.3 units). There were no statistically significant differences in the mean difference in change for the secondary outcomes of forced expiratory volume in the first second (0.0 L; 95% CI, -0.1 to 0.1 L), asthma-related quality of life (-0.1; 95% CI, -0.3 to 0.1), or rate of episodes of poor asthma control (relative risk, 1.2; 95% CI, 0.9-1.5). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole vs placebo was observed for any asthma outcome. Children treated with lansoprazole reported more respiratory infections (relative risk, 1.3 [95% CI, 1.1-1.6]). CONCLUSION In this trial of children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, compared with placebo, improved neither symptoms nor lung function but was associated with increased adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00442013.

Pharmacogenetics of asthma

Purpose of review Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs. Recent findings Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers. Summary Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine.

Efficacy and safety of inhaled fluticasone propionate chlorofluorocarbon in 2- to 4-year-old patients with asthma: results of a double-blind, placebo-controlled study

BACKGROUND Current asthma guidelines recommend inhaled glucocorticoids administered via pressurized metered-dose inhaler (MDI) with a holding chamber as the preferred therapy for young children with asthma. OBJECTIVE To evaluate the efficacy and safety of fluticasone propionate chlorofluorocarbon MDI use in preschool-aged children with asthma. METHODS Randomized, double-blind, placebo-controlled, parallel-group study of 332 children aged 24 to 47 months with asthma. Fluticasone propionate chlorofluorocarbon, 44 or 88 microg twice daily, or placebo (chlorofluorocarbon propellant alone) administered for 12 weeks via MDI with a valved holding chamber and an attached face mask. The primary efficacy measure was average change in 24-hour daily asthma symptom scores. Safety assessments included adverse events, 12-hour urinary cortisol excretion, and growth. RESULTS Treatment failure (ie, asthma exacerbation) occurred in approximately half as many fluticasone propionate-treated patients (13%-14%) as placebo-treated patients (24%). Compared with placebo users, patients treated with fluticasone propionate, 88 microg twice daily, had a 13% greater improvement in the mean proportion of symptom- and albuterol-free days (P = .02); asthma symptom scores and albuterol use were also significantly reduced. Patients treated with fluticasone propionate, 44 microg twice daily, had greater improvements than placebo-treated patients; however, differences did not reach statistical significance. At end point, the growth velocities of fluticasone propionate-treated patients were within the range of those of placebo-treated patients. No clinically relevant changes in 12-hour overnight urinary cortisol excretion were observed. CONCLUSION Compared with placebo use, fluticasone propionate, 88 microg administered twice daily, significantly reduced asthma exacerbations, asthma symptoms, and rescue albuterol use and was well tolerated, with no clinically relevant systemic effects, as measured by growth velocity or 12-hour urinary cortisol excretion levels.

EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency

BACKGROUND EUR-1008 (Zenpep [pancrelipase]) is a new, enteric-coated, porcine-derived pancreatic enzyme product (PEP) developed for the treatment of cystic fibrosis (CF) patients with malabsorption associated with exocrine pancreatic insufficiency (EPI). Unlike currently marketed PEPs, EUR-1008 contains the label-claimed lipase content. Safety and efficacy were assessed in younger (<7 years) and older (> or =7 years) CF patients with EPI. METHODS Two multicenter studies were conducted: a randomized, double-blind, placebo-controlled, crossover trial in patients > or =7 years of age (N=34) and a supplemental, open-label study in children <7 years of age (N=19). Use of any medications altering gastric pH/motility was prohibited during the studies. Outcome measures in the randomized trial included changes in the coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), and signs/symptoms of malabsorption for EUR-1008 vs. placebo. Outcome measures in the supplemental study included safety and response (defined as no steatorrhea and no overt signs/symptoms of malabsorption) to EUR-1008 vs. previous enzyme treatment. RESULTS In the randomized trial, EUR-1008 treatment compared to placebo resulted in a significantly higher mean CFA (88.3% vs. 62.8%, respectively) and CNA (87.2% vs. 65.7%, respectively) (both p<0.001) and reduced the incidence of malabsorption signs and symptoms in 32 evaluable patients. In the supplemental study, 11 of 19 patients met the criteria for responder with EUR-1008 at the end of the study vs. 10 of 19 patients at screening (previous PEP), and improvements in clinical symptoms were reported with EUR-1008 treatment. EUR-1008 was safe and well tolerated, and no serious drug-related AEs were reported in either study. CONCLUSIONS EUR-1008 was safe, well tolerated, and effective in CF patients of all ages with EPI-associated malabsorption in two clinical trials. Treatment led to clinically and statistically significant improvements in CFA and CNA in the randomized study, and control of malabsorption and clinical symptoms in both studies.

Exhaled nitric oxide measurements in childhood asthma : Techniques and interpretation

In this review, we outline the role of nitric oxide in airway inflammation in children with asthma. We also discuss the various methods reported for measuring exhaled nitric oxide and provide some insight as to the pros and cons and pitfalls of these techniques. Guidelines for measurements of exhaled nitric oxide based on our experience are provided, as well as suggestions for the use of this technique as a new “airway inflammation test.” Pediatr Pulmonol. 1999; 28:282–296.

Montelukast dose selection in 6- to 14-year-olds : Comparison of single-dose pharmacokinetics in children and adults

Montelukast, an oral leukotriene‐receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once‐daily 10 mg dose (film‐coated tablet) was selected as the optimal adult dose based on dose‐ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film‐coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose‐ranging studies in children. Therefore, the dose of montelukast for 6‐ to 14‐ year‐old children was selected by identifying the chewable tablet dose of montelukast yielding a single‐dose area under the plasma concentration‐time curve (AUC) comparable to that achieved with the adult 10 mg film‐coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6‐ to 14‐year‐old children with asthma.

Theophylline attenuation of airway responses to allergen: Comparison with cromolyn metered-dose inhaler

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 micrograms/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.

Fluticasone propionate and salmeterol administered via Diskus compared with salmeterol or fluticasone propionate alone in patients suboptimally controlled with short-acting β2-agonists

BACKGROUND Optimal therapy for many patients with persistent asthma requires control of both main components of this disease: inflammation and bronchoconstriction. OBJECTIVES To compare the efficacy and safety of initiating maintenance therapy with an inhaled, long-acting beta2-agonist and an inhaled corticosteroid administered from a single device with that of the individual agents alone. METHODS A 12-week, randomized, double-blind study was conducted in patients 12 years and older with persistent asthma who were symptomatic while taking as-needed, short-acting beta2-agonists alone. Treatments were administered twice daily via the Diskus device: salmeterol, 50 microg; fluticasone propionate, 100 microg; or fluticasone propionate, 100 microg, with salmeterol, 50 microg. RESULTS Of 555 patients screened, 267 were randomly assigned to treatment. At end point, fluticasone propionate and salmeterol significantly increased predose forced expiratory volume in 1 second (FEV1) compared with salmeterol alone (0.51 +/- 0.05 L vs 0.38 +/- 0.04 L, P = .04). Fluticasone propionate and salmeterol significantly increased area under the serial FEV1 curve at treatment week 12 relative to predose FEV1 (baseline) on treatment day 1 (AUCb1, 8.4 +/- 0.6 L/h; P < or = .02) compared with salmeterol (6.2 +/- 0.5 L/h) and fluticasone propionate (7.0 +/- 0.6 L/h). Fluticasone propionate and salmeterol were significantly (P < or = .02) more effective than the individual agents used alone in improving morning and evening peak expiratory flow rate and asthma symptoms. In addition, fluticasone propionate and salmeterol effectively reduced rescue albuterol use (P < or = .04). All treatments were well tolerated. CONCLUSIONS In patients symptomatic while taking short-acting beta2-agonists alone, initial maintenance treatment of the 2 main components of asthma, inflammation and smooth muscle dysfunction, with fluticasone propionate and salmeterol, 100 and 50 microg, administered via the Diskus results in greater improvements in overall asthma control compared with treatment of either component alone.

Montelukast: Data from Clinical Trials in the Management of Asthma

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of montelukast, a leukotriene receptor antagonist used to treat asthma, and to discuss the therapeutic role of montelukast as long-term medication and difficulties associated with the management of asthma. DATA SOURCES: A MEDLINE search (up to May 1999) was conducted to identify relevant English-language publications, including preclinical studies, clinical trials, and recent reviews. STUDY SELECTION: All available published reports of controlled, clinical trials of montelukast in adults and children with asthma were summarized, including pharmacokinetic and pharmacologic effects of montelukast. DATA EXTRACTION: Information on the safety and efficacy of montelukast was evaluated on the basis of patient selection, study design, methodology, and statistical significance as compared with placebo or inhaled corticosteroid treatment. DATA SYNTHESIS: Montelukast is approved for the prophylaxis and chronic treatment of asthma at a dose of 10 mg once daily for adolescents (=15 y) and adults and 5 mg once daily for children (6–14 y). In placebo-controlled clinical trials, montelukast significantly improved pulmonary lung function (as measured by forced expiratory volume in 1 sec), significantly reduced β2-agonist use, and significantly improved patient-reported end points in adults and children (=6 y) with chronic asthma. In adults, a similar magnitude of improvement in lung function is seen with or without inhaled corticosteroid use; the effects of montelukast may be additive to those of inhaled corticosteroids and permit the reduction of the required dose of inhaled corticosteroids. In cases of exercise-induced asthma (adults and children), montelukast treatment attenuates the fall in pulmonary function following exercise. It attenuates both the early- and late-phase responses of asthma after allergen inhalation. Improvements in asthma control are similar in asthmatic patients who are aspirin-sensitive or not aspirin-sensitive and can be seen within one day of treatment. Tolerance does not develop, and the adverse events do not differ from those of placebo. CONCLUSIONS: Montelukast is indicated for the prophylaxis of chronic asthma in adults and children (=6 y). It may be considered for use as first-line therapy in patients with mild persistent asthma or for additional control in patients who are still symptomatic while receiving treatment with inhaled corticosteroids. It may also be used for additional control in aspirin-sensitive asthmatic patients. Consideration may be given for using montelukast to allow tapering of the dose of inhaled corticosteroids while maintaining clinical stability. Chronic treatment with montelukast can provide additional control of symptoms during exercise, but inhaled β2-agonists remain first-line therapy for prophylaxis and treatment.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).