Richard C. Ahrens

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

RATIONALE Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation. OBJECTIVES This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6-11 years with a G551D-CFTR mutation on at least one allele. METHODS Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies. MEASUREMENTS AND MAIN RESULTS Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was -53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with www.clinicaltrials.gov (NCT00909727).

Relative efficacy of maintenance therapy with theophylline, inhaled albuterol, and the combination for chronic asthma

The relative benefit of maintenance therapy with theophylline, inhaled albuterol, and the combination was examined in 18 adolescents and adults with chronic asthma during a 3-month, randomized, double-blind, crossover trial. Theophylline and combination regimens were associated with significantly fewer days with symptoms (52% and 55%) than albuterol (72%). The greater frequency of symptoms during the albuterol regimen was increasingly apparent more than 4 hours after albuterol doses and was greatest between 4 and 8 A.M. Albuterol transiently inhibited histamine-induced bronchospasm to a much greater degree than did theophylline, and combining the drugs produced at least an additive effect. The effect of albuterol was completely absent by 4 hours, however, whereas that of theophylline persisted. Thus, in spite of greater acute effects on the airways, the transient duration of effect from inhaled albuterol appears to limit its usefulness as maintenance therapy, especially for patients with nocturnal symptoms.

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency

Use of bronchial provocation with histamine to compare the pharmacodynamics of inhaled albuterol and metaproterenol in patients with asthma

Because measurement of effects on airway responsiveness may have advantages over the study of bronchodilatation for the evaluation of the effects of inhaled beta 2-agents, we developed a method using airway responsiveness for the independent quantitation of the relative potencies and rates of decline in effect of these drugs. This methodology was applied to the evaluation and comparison of inhaled metaproterenol and albuterol. The effects of two different doses of each drug (one and two inhalations of albuterol and two and four inhalations of metaproterenol from commercially available metered-dose inhalers) were compared with a double-blind, randomized, placebo-controlled, crossover study of 13 subjects. The effects of metaproterenol and albuterol declined at rates that were not significantly different. However, based on the effects on activity ratio at 30 minutes, each puff of metaproterenol was an estimated 0.37 times as potent as each puff of albuterol (95% confidence limits, 0.22 to 0.52). In recommended two puff doses, measurable effects of albuterol persisted longer than effects of metaproterenol. However, this appears to be because of a greater initial effectiveness of two puffs of albuterol rather than differences in the rates at which the effects of the two drugs declined with time. Airway responsiveness thus appears to be a useful tool for evaluating inhaled beta 2-agonists and designing beta 2-agonist dosing regimens.

Randomized Trial of Biofilm Testing to Select Antibiotics for Cystic Fibrosis Airway Infection

In cystic fibrosis (CF), conventional antibiotic susceptibility results correlate poorly with clinical outcomes. We hypothesized that biofilm testing would more accurately reflect the susceptibilities of bacteria infecting CF airways.

Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion

Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral → apical Cl− ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl− conductance is mediated by altered cystic fibrosis transmembrane conductance regulator expression and activity. Generation of iIL-13Tg/Il13rα1−/−, iIL-13Tg/Il13rα2−/−, and iIL-13Tg/Stat6−/− mice revealed that IL-13-mediated dysregulation of epithelial architecture and Cl− conductance is dependent on IL-13Rα1 and STAT-6. These observations demonstrate a central role for the IL-13/IL-13Rα1 pathway in the regulation of intestinal epithelial cell Cl− secretion via up-regulation of cystic fibrosis transmembrane conductance regulator, suggesting an important role for this pathway in secretory diarrhea.

Extrapulmonary effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma

The extrapulmonary effects of slow-release theophylline and an inhaled beta 2-agonist (albuterol) were examined separately and in combination among 18 adults and adolescents with asthma during a 3-month randomized, double-blind, crossover trial. Although neither global impressions nor daily diaries revealed differences in adverse effects, a structured questionnaire completed at the end of each regimen suggested a small but statistically significant increase in nausea and depressive and caffeine-like symptoms during the theophylline-containing regimens. Theophylline was also associated with improved verbal learning but decreased motor steadiness. Metabolic effects associated with theophylline included lower serum bicarbonate, greater urinary calcium excretion, and higher serum calcium, uric acid, and creatinine. Albuterol was associated with lower neutrophil counts and lower serum theophylline concentrations. There were no drug-induced effects on cardiac rhythm.

Equivalence considerations for orally inhaled products for local action-ISAM/IPAC-RS European Workshop report.

The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified.

A bioassay for topical and systemic effect of three inhaled corticosteroids

Comparisons of relative potency for the three inhaled corticosteroids in the United States are limited to assessment of skin blanching.

Resistin-Like Molecule α Decreases Glucose Tolerance during Intestinal Inflammation

Resistin-like molecule α (Relm-α) is a secreted cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-β, and Relm-γ. Resistin was initially defined based on its insulin resistance activity, but the family members are highly up-regulated in various inflammatory states, especially those involving intestinal inflammation. In this study, we report the role of Relm-α at baseline and following an experimental model of colitis. Relm-α was readily detected in the serum at baseline (4–5 ng/ml), and its level was regulated by energy uptake. Retnla−/− mice had decreased baseline circulating leptin levels, but displayed normal glucose, glucose clearance, and insulin levels. Following exposure to the oral innate trigger dextran sodium sulfate (DSS), a nonredundant proinflammatory role for Relm-α was uncovered as Retnla−/− mice were markedly protected from DSS-induced disease activity and histopathological features. Relm-α regulated eosinophil-directed cytokines (e.g., IL-5, CCL11/eotaxin-1, and CCL5/RANTES) and IL-17 ex vivo. Consistently, DSS-treated Retnla−/− mice displayed substantially decreased eosinophil accumulation and decreased phosphorylation of NF-κB, ERK1/2, and p38 in macrophages and eosinophils. Following DSS exposure, serum level of Relm-α was up-regulated, and DSS-treated Retnla−/− mice were markedly protected from hyperglycemia induced by glucose injection independent of changes in insulin levels. Retnla−/− mice were protected from increases in gut hormone serum levels of gastric inhibitory polypeptide and peptide YY that were induced following DSS treatment. These findings demonstrate a central proinflammatory role for Relm-α in the regulation of colonic inflammation and a novel link between colonic injury, glucose tolerance, and energy intake.