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 (PD₂₀FEV₁), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E₂and 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 β₂-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 FEV₁compared to placebo (p < 0.01), and reduced morning waking with asthma from baseline after two weeks (p < 0.05). Similarly in Group II, FEV₁improved compared to placebo (p < 0.05), and there were early within-treatment group improvements in morning PEF, β₂-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 FEV₁compared with placebo (p ≤ 0.05) and increased nocturnal awakenings in Group II (p < 0.05). There were no changes in PD₂₀FEV₁, 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

Allergen immunotherapy for allergic asthma: a systematic overview of systematic reviews

Background: there is clinical uncertainty about the effectiveness and safety of allergen immunotherapy (AIT) for the treatment of allergic asthma.Objectives: to undertake a systematic overview of the effectiveness, cost-effectiveness and safety of AIT for the treatment of allergic asthma.Methods: we searched nine electronic databases from inception to October 31, 2015. Systematic reviews were independently screened by two reviewers against pre-defined eligibility criteria and critically appraised using the Critical Appraisal Skills Programme quality assessment tool for systematic reviews. Data were descriptively and thematically synthesized.Results: we identified nine eligible systematic reviews; these focused on delivery of AIT through the following routes: subcutaneous (SCIT; n = 3); sublingual (SLIT; n = 4); and both SCIT and SLIT (n = 2). This evidence found that AIT delivered by SCIT and SLIT can improve medication and symptom scores and measures of bronchial hyper-reactivity. The impact on measures of lung function or asthma control was however less clear. We found no systematic review level evidence on the cost-effectiveness of SCIT or SLIT. SLIT had a favorable safety profile when compared to SCIT, particularly in relation to the risk of systemic reactions.Conclusions: AIT has the potential to achieve reductions in symptom and medication scores, but there is no clear or consistent evidence that measures of lung function can be improved. Bearing in mind the limitations of synthesizing evidence from systematic reviews and the fact that these reviews include mainly dated studies, a systematic review of current primary studies is now needed to update this evidence base, estimate the effectiveness of AIT on asthma outcomes and to investigate the relative effectiveness, cost-effectiveness and safety of SCIT and SLIT

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding

How safe are the biologicals in treating asthma and rhinitis?

A number of biological agents are available or being investigated for the treatment of asthma and rhinitis. The safety profiles of these biologic agents, which may modify allergic and immunological diseases, are still being elucidated. Subcutaneous allergen immunotherapy, the oldest biologic agent in current use, has the highest of frequency of the most serious and life-threatening reaction, anaphylaxis. It is also one of the only disease modifying interventions for allergic rhinitis and asthma. Efforts to seek safer and more effective allergen immunotherapy treatment have led to investigations of alternate routes of delivery and modified immunotherapy formulations. Sublingual immunotherapy appears to be associated with a lower, but not zero, risk of anaphylaxis. No fatalities have been reported to date with sublingual immunotherapy. Immunotherapy with modified formulations containing Th1 adjuvants, DNA sequences containing a CpG motif (CpG) and 3-deacylated monophospholipid A, appears to provide the benefits of subcutaneous immunotherapy with a single course of 4 to 6 preseasonal injections. There were no serious treatment-related adverse events or anaphylaxis in the clinical trials of these two immunotherapy adjuvants. Omalizumab, a monoclonal antibody against IgE, has been associated with a small risk of anaphylaxis, affecting 0.09% to 0.2% of patients. It may also be associated with a higher risk of geohelminth infection in patients at high risk for parasitic infections but it does not appear to affect the response to treatment or severity of the infection

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

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis

Background: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR).Methods: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus.Results: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR.Conclusion: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding. </p

Development and design of dual-band, multi-function remote sensing antennas

This dissertation details the theoretical development, design, fabrication, and testing of two remote sensing antennas. The antennas operate in Ku and Ka bands and must support multiple beams, polarizations, and frequencies with a single aperture. The first antenna, developed for NASA\u27s High-Altitude Imaging Wind and Rain Airborne Profiler, is a single, offset-fed reflector that supports dual-band beams incident at 30° and 40° off-nadir. The antenna uses two compact, dual-band feeds moved away from the reflector\u27s focal point to meet the dual beam requirement. The radar is to be flown on the Global Hawk Uninhabited Aerial Vehicle which has a small payload bay requiring the feeds to be both rugged and compact. The second antenna, developed for Remote Sensing Solutions\u27 Dual-Wavelength Precipitation Radar, is a dual-offset Gregorian reflector. The antenna supports a single, dual-band, beam with dual-polarization at each band. Additionally, the antenna has high polarization purity and matched half power beamwidths at Ku and Ka bands. The strict requirements of the antenna are met by precisely controlling feed radiation characteristics. The two antennas necessitated several advances in feed design. A foam sleeve is demonstrated as an effective method to reduce the beamwidth of a tapered dielectric rod antenna. The foam sleeve is an attractive design because it allows dual-band feeds where a corrugated horn is used to control radiation at lower frequencies and the sleeve corrected rod is used to control the upper band. By judiciously choosing sleeve material, independent control of the radiation pattern and phase center at each band is achieved allowing higher performance feeds. This dissertation also focuses on new developments in the backend design of feeds. Specifically, the use of tuning arms in the feed backend and double ridged waveguide to couple the signal into the feed allow more compact designs with greater bandwidth