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Biomedical subjects

Richard Ahrens

Publications and source records attributed to Richard Ahrens.

9 recordsLinked to original sources
PubMed2006

ICAM-1-dependent pathways regulate colonic eosinophilic inflammation.

Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal (EGID) diseases. Central to eosinophil migration into the gastrointestinal tract are the integrin-mediated interactions with adhesion molecules. Although the mechanisms regulating eosinophil homing into the small intestine have begun to be elucidated, the adhesion pathways responsible for eosinophil trafficking into the large intestine are unknown. We investigated the role of adhesion pathways in eosinophil recruitment into the large intestine during homeostasis and disease. First, using a hapten-induced colonic injury model, we demonstrate that in contrast to the small intestine, eosinophil recruitment into the colon is regulated by a beta7 -integrin addressin cell adhesion molecule-1-independent pathway. Characterization of integrin expression on colonic eosinophils by flow cytometry analysis revealed that colonic CC chemokine receptor 3+ eosinophils express the intercellular adhesion molecule-1 (ICAM-1) counter-receptor integrins alphaL, alphaM, and beta2. Using ICAM-1-deficient mice and anti-ICAM-1 neutralizing antibodies, we show that hapten-induced colonic eosinophilic inflammation is critically dependent on ICAM-1. These studies demonstrate that beta2 -integrin/ICAM-1-dependent pathways are integral to eosinophil recruitment into the colon during GI inflammation associated with colonic injury.

Animals↗
PubMed2006

Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.

BACKGROUND: Aztreonam lysinate for inhalation (AI) is a novel monobactam formulation being investigated for pulmonary Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF). METHODS: Pre-clinical studies investigated the pre- and post-nebulization activity of AI and its activity in the presence of CF sputum. A double-blind, placebo-controlled, dose-escalation trial determined pharmacokinetics and tolerability of AI in subjects with CF. Single daily escalating doses of AI 75, 150, or 225 mg, or placebo were self-administered using an eFlow Electronic Nebulizer. Sputum samples were collected up to 4 hr and blood samples up to 8 hr post-dose. RESULTS: AI activity against multiple CF isolates was retained after nebulization via eFlow, and activity was not inhibited by CF sputum. All 12 adult subjects and 11/12 adolescents tolerated all AI doses. One patient had an asymptomatic FEV1 decrease > 20% with the 150 mg dose. Median aztreonam sputum concentrations in adults 10 min after AI 75, 150, and 225 mg were 383, 879, and 985 microg/g, respectively. Median sputum concentrations in adolescents 10 min after AI 75, 150, and 225 mg were 324, 387, and 260 microg/g, respectively. Systemic exposure to AI was low. Plasma pharmacokinetics in adults receiving AI 75 mg were Cmax = 419 ng/g, Tmax = 0.99 hr, t1/2 = 2.1 hr. Aztreonam concentrations in sputum were at or above the MIC50 for at least 4 hr post-dose. CONCLUSION: These data support the continued development of AI for treatment of pulmonary infections in patients with CF.

Administration, Inhalation↗
PubMed2006

Resistin-like molecule beta regulates innate colonic function: barrier integrity and inflammation susceptibility.

BACKGROUND: Resistin-like molecule (RELM) beta is a cysteine-rich cytokine expressed in the gastrointestinal tract and implicated in insulin resistance and gastrointestinal nematode immunity; however, its function primarily remains an enigma. OBJECTIVE: We sought to elucidate the function of RELM-beta in the gastrointestinal tract. METHODS: We generated RELM-beta gene-targeted mice and examined colonic epithelial barrier function, gene expression profiles, and susceptibility to acute colonic inflammation. RESULTS: We show that RELM-beta is constitutively expressed in the colon by goblet cells and enterocytes and has a role in homeostasis, as assessed by alterations in colon mRNA transcripts and epithelial barrier function in the absence of RELM-beta. Using acute colonic inflammatory models, we demonstrate that RELM-beta has a central role in the regulation of susceptibility to colonic inflammation. Mechanistic studies identify that RELM-beta regulates expression of type III regenerating gene (REG) (REG3beta and gamma), molecules known to influence nuclear factor kappaB signaling. CONCLUSIONS: These data define a critical role for RELM-beta in the maintenance of colonic barrier function and gastrointestinal innate immunity. CLINICAL IMPLICATIONS: These findings identify RELM-beta as an important molecule in homeostatic gastrointestinal function and colonic inflammation, and as such, these results have implications for a variety of human inflammatory gastrointestinal conditions, including allergic gastroenteropathies.

Animals↗
PubMed2006

Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients.

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

Adolescent↗
PubMed2005

Randomized, double-blind, placebo-controlled, dose-escalating study of aerosolized interferon gamma-1b in patients with mild to moderate cystic fibrosis lung disease.

Interferon gamma-1b (IFN-gamma1b) is a pleiotropic cytokine with immunomodulatory activities that could decrease bacterial burden, inflammation, and obstruction in patients with CF. Patients with CF (> or =12 years old, FEV1 > or =40% predicted) were randomly assigned to sequential dose cohorts inhaling 500 microg IFN-gamma1b, 1,000 microg IFN-gamma1b, or placebo by Respirgard II nebulizer thrice weekly for 12 weeks. Sputum bacterial density and spirometry were measured. Safety, antibiotic use, hospitalization, and sputum neutrophils, elastase, DNA, IL-8, and myeloperoxidase were also evaluated. Sixty-six patients (mean age, 24 years, with mean baseline FEV1 of 74 +/- 20 (SD) percent predicted) were studied. One patient had bronchospasm after the first dose of IFN-gamma1b; the overall withdrawal rate was 15% (5 in the placebo group, 2 in the 500-microg IFN-gamma1b group, and 3 in the 1,000 microg IFN-gamma1b group). The 500-microg IFN-gamma1b dose was well-tolerated, but the 1,000-mug dose cohort, who had a higher baseline bacterial density than placebo patients (mean difference, 1.2 log(10) CFU/g sputum, 95% confidence interval (CI), 0.1,2.8, P=0.04), had 24% more hospitalizations for exacerbation than placebo patients (95% CI, 2,45%, P=0.05). There was a 0.12-l difference between the 500-microg IFN-gamma1b and placebo groups with respect to the 12-week change in FEV1 (active group minus placebo group, 95% CI, -0.03,0.26, P=0.11), as compared to a 0.01-l difference between the 1,000-microg IFN-gamma1b and placebo groups (95% CI, -0.16,0.17, P=0.96). No effects of IFN-gamma1b were seen in sputum bacterial density or inflammatory biomarkers at 12 weeks. Aerosolized IFN-gamma1b did not improve pulmonary function, reduce sputum bacterial density, or affect inflammatory sputum markers in patients with mild-moderate lung disease.

Administration, Inhalation↗
PubMed2005

Response to nonprescription epinephrine inhaler during nocturnal asthma.

BACKGROUND: Many health care professionals believe that a nonprescription epinephrine metered-dose inhaler is less effective and shorter acting and has more cardiovascular adverse effects than prescription beta2-agonists. OBJECTIVE: To determine if increasing the epinephrine dose improves efficacy safely. METHODS: Eight patients with nocturnal asthma (age range, 20-46 years) were treated in a randomized, crossover manner on 2 different nights while sleeping in a clinical research center. On awakening from asthma symptoms, 2, 4, and 8 actuations of epinephrine or albuterol were administered at 17-minute intervals (14 cumulative actuations). Forced expiratory volume in 1 second (FEV1), asthma symptoms, and systemic effects were measured before the first dose, during the 9- to 17-minute period after each dose, and 30 minutes after the last dose. RESULTS: The mean +/- SD FEV1 at the onset of symptoms was 45% +/- 11% and 44% +/- 12% predicted before epinephrine and albuterol, respectively, and increased to a maximum of 86% +/- 11% and 93% +/- 10%, respectively (P = .04). Symptoms decreased as FEV1 improved and did not return after either treatment; 6 patients were symptom free after 14 cumulative actuations of epinephrine compared with 6 cumulative actuations of albuterol. Heart rate decreased to 71 +/- 10/min after epinephrine but increased to 92 +/- 14/min after albuterol (P = .001). After the last dose, serum potassium concentration was 3.6 +/- 0.3 micromol/L after epinephrine and 3.2 +/- 0.4 micromol/L after albuterol (P = .01). CONCLUSION: Epinephrine was nearly as effective as albuterol in terminating an acute episode of airway obstruction but without cardiovascular effects in these otherwise healthy young adults.

Administration, Inhalation↗
PubMed2004

Asthma prevalence and morbidity among rural Iowa schoolchildren.

BACKGROUND: There are conflicting findings about the prevalence of asthma among farm and nonfarm children. OBJECTIVES: We sought to estimate asthma prevalence and morbidity and determine differences between farm and nonfarm children. METHODS: The study population consisted of all children aged 6 to 14 years enrolled in 10 school districts in 2 noncontiguous rural Iowa counties from 2000 through 2002. The mailed parental screening questionnaire included the International Study of Asthma and Allergies in Childhood core questionnaire, items from the Functional Severity Index, and items on physician diagnosis and medication and urgent care use. RESULTS: The response rate was 86.6%. The 12-month prevalence of wheeze was 19.1%. Self-reported physician diagnosis of asthma was reported by 13.4%. On multivariable analysis controlling for age, sex, and county, children who lived on farms were less likely than those who lived in town to have ever wheezed (odds ratio, 0.71; 95% CI, 0.58-0.87) or to have wheezed during the past year (odds ratio, 0.77; 95% CI, 0.60-0.98). However, this protective association with farming was only observed in one of the study counties. Among those who wheezed, farm and nonfarm children were equally likely to have been given a diagnosis of asthma and had comparable morbidity. CONCLUSION: By using a standardized questionnaire with a high response rate in this large, rural, population-based study, asthma prevalence rivaled that in large Midwestern cities. Unmeasured risk factors might account for the apparent protective effect in Keokuk County. These findings cast doubt on a protective effect of rural life for the development of childhood asthma.

Adolescent↗
PubMed2004

Response to inhaled albuterol during nocturnal asthma.

BACKGROUND: During conventional daytime studies of beta(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 [<0.25, 2] puffs; 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 beta(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.

Administration, Inhalation↗