3 research outputs found
Tolerance and rebound with zafirlukast in patients with persistent asthma
<p>Abstract</p> <p>Background</p> <p>The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined.</p> <p>Objective</p> <p>To look for any evidence of tolerance and potential for short-term clinical worsening on LRA withdrawal. Outcome measures included changes in; airway hyperresponsiveness to inhaled methacholine (PD<sub>20</sub>FEV<sub>1</sub>), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E<sub>2 </sub>and exhaled nitric oxide (eNO) levels.</p> <p>Methods</p> <p>A double blind, placebo-controlled study of zafirlukast, 20 mg twice daily over 12 weeks in 21 asthmatics taking β<sub>2</sub>-agonists only (Group I), and 24 subjects treated with ICS (Group II).</p> <p>Results</p> <p>In Group I, zafirlukast significantly improved morning PEF and FEV<sub>1</sub>compared to placebo (p < 0.01), and reduced morning waking with asthma from baseline after two weeks (p < 0.05). Similarly in Group II, FEV<sub>1 </sub>improved compared to placebo (p < 0.05), and there were early within-treatment group improvements in morning PEF, β<sub>2</sub>-agonist use and asthma severity scores (p < 0.05). However, most improvements with zafirlukast in Group I and to a lesser extent in Group II deteriorated toward baseline values over 12 weeks. In both groups, one week following zafirlukast withdrawal there were significant deteriorations in morning and evening PEFs and FEV<sub>1 </sub>compared with placebo (p ≤ 0.05) and increased nocturnal awakenings in Group II (p < 0.05). There were no changes in PD<sub>20</sub>FEV<sub>1</sub>, sputum CysLT concentrations or exhaled nitric oxide (eNO) levels. However, blood neutrophils significantly increased in both groups following zafirlukast withdrawal compared to placebo (p = 0.007).</p> <p>Conclusion</p> <p>Tolerance appears to develop to zafirlukast and there is rebound clinical deterioration on drug withdrawal, accompanied by a blood neutrophilia.</p
Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis
Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75432/1/j.1365-2222.2006.02498.x.pd
Leukotriene B(4) Augments Neutrophil Phagocytosis of Klebsiella pneumoniae
Neutrophils play a critical role in the clearance of bacteria from the lung and other organs by their capacity for phagocytosis and killing. Previously, we identified an important role for the leukotrienes in rat alveolar macrophage phagocytosis of Klebsiella pneumoniae. In this report, we explored the possibility that the leukotrienes play an important role in phagocytosis by neutrophils as well. Inhibition of endogenous leukotriene synthesis by 5-lipoxygenase knockout in mice or by pharmacologic means in human peripheral blood neutrophils attenuated phagocytosis of opsonized K. pneumoniae. Reduced phagocytosis was also observed in human neutrophils pretreated with a leukotriene B(4) receptor but not a cysteinyl-leukotriene receptor antagonist. While leukotriene B(4) reconstituted defective phagocytosis in leukotriene-deficient neutrophils and enhanced phagocytosis in neutrophils capable of leukotriene synthesis, leukotriene C(4), leukotriene D(4), 5-hydroperoxyeicosatetraenoic acid, and 5-oxo-eicosatetraenoic acid were ineffective. To determine the opsonin dependence of the leukotriene B(4) augmentation of phagocytosis, we assessed the ability of leukotriene B(4) to modulate neutrophil phagocytosis and the adherence of sheep erythrocytes opsonized with immunoglobulin G or the complement fragment C3bi. While leukotriene B(4) augmented both Fc receptor- and complement receptor-mediated phagocytosis, increased adherence to leukotriene B(4)-treated neutrophils was limited to complement opsonized targets. In conclusion, we have identified a novel role for leukotriene B(4) in the augmentation of neutrophil phagocytosis mediated by either the Fc or complement receptor