Oral antihistamines that target the histamine receptor–1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise. Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post-dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396). PF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events. PF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls.
There is a growing interest in anthropology towards identifying and documenting the ways in which people have modified landscapes and ecosystems through time. Previous research has focused predominantly on terrestrial modification, whereas recently, research has turned towards aquatic environments. Examples range from the tidal fish pens of Hawai'i to fish weir complexes and clam gardens on the Northwest Coast. Scholars are beginning to apply the term human ecosystem engineering to the practices linked to wetland landscape modifications. Evidence of these practices can contribute to understanding optimization, cultivation, and modification of aquatic environments on a landscape level. However, some regions have received more consideration than others; the backwater wetlands of the Lower Columbia are minimally studied.
The enzyme, arginase, converts L-arginine into L-ornithine and urea, and has been implicated in the pathogenesis of lung diseases, related to dysregulation of L-arginine metabolism and remodeling. Allergic asthma is a chronic condition characterized by inflammation, lung remodeling and airways hyperresponsiveness (AHR). Increased expression of arginase may contribute to AHR in asthma by reducing L-arginine bioavailability for the nitric oxide synthase (NOS) isozymes, thus, limiting the production of the endogenous bronchodilator, nitric oxide (NO). Reduction of intracellular L-arginine concentrations as a consequence of augmented arginase expression and activity may also promote NOS uncoupling, resulting in increased formation of peroxynitrite, a powerful oxidant that promotes bronchoconstriction and inflammation. In chronic asthma, increased arginase expression may also contribute to airways remodeling, through increased synthesis of L-ornithine, and hence the production of polyamines and L-proline, which are involved in cell proliferation and collagen deposition, respectively. New drugs targeting the arginase pathway could have therapeutic benefits in asthma. This review focuses on recent developments in our understanding of the role of arginase in AHR, inflammation and remodeling, highlighting studies that advance our knowledge of L-arginine dysregulation in human asthma and animal studies that explore the therapeutic potential of arginase inhibition.
Objective: This study compared the efficacy of 1000 mg of paracetamol combined with 60 mg of pseudoephedrine, with that of either paracetamol or pseudoephedrine alone and placebo for the treatment of symptomatic URTI.Research design and methods: A double‐blind, parallel group study was performed on 305 patients with URTI (nasal airflow resistance [NAR] of > 0.25 Pa cm3 s and a global pain score of at least moderate intensity). NAR and pain relief/intensity scores were measured over 4 h after initial dose. Patients then dosed up to three times daily for 3 days and recorded nasal congestion and pain intensity scores.Main outcome measures: Nasal airflow conductance (NAC) and pain relief after the initial dose were primary objectives. NAC was calculated from NAR. Pain relief was measured on a 5‐point verbal rating scale (VRS) and pain intensity and nasal congestion on a 4‐point VRS. Data were analysed using analysis of covariance. Safety was assessed by adverse events.Results: A single dose of the combination was superior to paracetamol and placebo for NAC ( p = 0.0001) and was superior to pseudoephedrine and placebo for pain relief ( p ≤ 0.048). Multiple doses of the combination were also superior to paracetamol and placebo for decongestion ( p ≤ 0.021) and were superior to pseudoephedrine and placebo for pain reduction ( p ≤ 0.0057). All treatments were well tolerated.Conclusions: The combination treatment provided a greater decongestant effect than either paracetamol or placebo and better pain relief than either pseudoephedrine or placebo. The additive effect of the combination was apparent for both single and multiple doses.
Context: Strong epidemiological evidence exists linking particulate matter (PM) exposures with hospital admissions of individuals for cardiopulmonary symptoms. The PM size is important in influencing the extent of infiltration into the respiratory tract and systemic circulation and directs the differential physiological impacts.
It has been known for 20 years that the production of nitric oxide (NO) by the NO synthase (NOS) isozymes is important in the maintenance of airways tone.Over the past decade, however, it has become increasingly apparent that competition between the NOS and arginase pathways for L-arginine, limits NO production.Imbalances between these pathways have been implicated in the airways hyperresponsiveness (AHR) of asthma.Thus, a delicate balance between the NOS and arginase pathways is maintained through the intracellular synthesis of endogenous NOS and arginase inhibitors.More recently, the liberation of methylarginines has emerged as an additional modifier of L-arginine uptake and metabolism in the lung.In this review we discuss the reciprocal regulation of the NOS and arginase pathways and methylarginines and their roles in the airways hyperresponsiveness of asthma.
Background Oral histamine receptor–1 antagonists, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Histamine receptor-3 antagonists, such as PF-03654764, reduce congestion in animals and have been proposed as novel therapeutics. Previous nasal allergen challenge studies of similar H1+H3 receptor antagonist combinations demonstrated reduced congestion. Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. The primary objective was to compare the effect of PF-03654764+fexofenadine to pseudoephedrine+fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objective of post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA).
