1,721,032 research outputs found
Why particle size should affect clinical response to inhaled therapy
No full textStudies with ?2-adrenergic agonists have shown that particle size and total dose are important determinants of optimum bronchodilation. Drug deposition in the airways is probably the most important factor for bronchodilation, since ?2-adrenoceptors and muscarinic M3 receptors are present mainly in the peripheral and central airways, respectively. Furthermore, clinical efficacy can be maintained while minimizing systemic exposure by selecting an appropriate particle size. Changes in lung function provide a means of monitoring the relationship between delivery of the bronchodilator and its efficacy, whereas there is no such immediate means of assessing antiinflammatory preventative therapy such as inhaled corticosteroids. Asthma is primarily an inflammatory disease but there are no simple tests to detect the accumulation of inflammatory cells and mediators. Data are presented to demonstrate the reduction of certain inflammatory markers in bronchial biopsy tissue taken from asthmatic patients after corticosteroid therapy. Measurement of inflammatory markers in both bronchial biopsy tissue and bronchoalveolar lavage samples may provide a way of monitoring the site of action and efficacy of inhaled corticosteroids in the future. Furthermore, it is envisaged that the effect of corticosteroid particle size on efficacy and systemic bioavailability may be investigated by exploiting these methods
Pharmacotherapy and airway remodelling in asthma?
No full textOver the last few decades attention has largely focused on airway inflammation in asthma, but more recently it has been appreciated that there are important structural airway changes which have been grouped together under the term "airway remodelling". It is only now that questions have been asked about the impact of treatment on these structural changes. This review examines the nature of these structural airway changes, the mechanisms of their generation, their potential consequences, and what is known about the ability of anti-asthma treatments to modulate these changes
Safety and tolerability profiles of intranasal antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis
No full textIntranasal corticosteroids and intranasal antihistamines are efficacious topical therapies in the treatment of allergic rhinitis. This review addresses their relative roles in the management of this disease, focusing on their safety and tolerability profiles. The intranasal route of administration delivers drug directly to the target organ, thereby minimising the potential for the systemic adverse effects that may be evident with oral therapy. Furthermore, the topical route of delivery enables the use of lower doses of medication. Such therapies, predominantly available as aqueous formulations following the ban of chlorofluorocarbon propellants, have minimal local adverse effects.Intranasal application of therapy can induce sneezing in the hyper-reactive nose, and transient local irritation has been described with certain formulations. Intranasal administration of corticosteroids is associated with minor nose bleeding in a small proportion of recipients. This effect has been attributed to the vasoconstrictor activity of the corticosteroid molecules, and is considered to account for the very rare occurrence of nasal septal perforation. Nasal biopsy studies do not show any detrimental structural effects within the nasal mucosa with long-term administration of intranasal corticosteroids. Much attention has focused on the systemic safety of intranasal application. When administered at standard recommended therapeutic dosage, the intranasal antihistamines do not cause significant sedation or impairment of psychomotor function, effects that would be evident when these agents are administered orally at a therapeutically relevant dosage.The systemic bioavailability of intranasal corticosteroids varies from <1% to up to 40–50% and influences the risk of systemic adverse effects. Because the dose delivered topically is small, this is not a major consideration, and extensive studies have not identified significant effects on the hypothalamic-pituitary-adrenal axis with continued treatment. A small effect on growth has been reported in one study in children receiving a standard dosage over 1 year, however. This has not been found in prospective studies with the intranasal corticosteroids that have low systemic bioavailability and therefore the judicious choice of intranasal formulation, particularly if there is concurrent corticosteroid inhalation for asthma, is prudent. There is no evidence that such considerations are relevant to shorter-term use, such as in intermittent or seasonal disease.Intranasal therapy, which represents a major mode of drug delivery in allergic rhinitis, thus has a very favourable benefit/risk ratio and is the preferred route of administration for corticosteroids in the treatment of this disease, as well as an important option for antihistaminic therapy, particularly if rapid symptom relief is required
Remodelling of the upper airways in allergic rhinitis: is it a feature of the disease
No full textThe traditional viewpoint that inflammation, owing to a genetic T-helper type 2 (Th2)-directed imbalance, is the cause of allergic rhinitis has meant that the potential coexistence of other genetic defects and the relevance of any airway remodelling changes to disease pathogenesis and persistence have received scant attention, and as such remain controversial areas. This is particularly so in view of the limited published work in this field, which has so far reported markedly conflicting findings. This review endeavours to outline what is known about the nature of the remodelling response within the upper airway in allergic rhinitis, in addition to highlighting specific areas where further research is warranted
The novel use of the human nasal epithelial cell line RPMI 2650 as an in vitro model to study the influence of allergens and cytokines on transforming growth factor-beta gene expression and protein release
No full textBackground The epithelial accumulation of mast cells is a feature of allergic rhinitis and this has been linked to the expression of the known mast cell chemoattractant transforming growth factor-? (TGF-?) at this site. Little is known concerning the regulation of TGF-? gene expression or protein release by nasal epithelial cells. To address this we have utilized the RPMI 2650 human nasal epithelial cell line, which has some features that closely resemble normal nasal epithelium and has been reported to secrete a TGF-?-like molecule.Objectives To investigate the regulation of TGF-? gene expression and protein secretion in RPMI 2650 nasal epithelial cells following exposure to allergens (house dust mite (HDM) and grass pollen) and mast cell associated T-helper type 2 (Th2) cytokines (IL-4, IL-13, and TNF-?).Methods Light and scanning electron microscopy was used to evaluate the morphology of RPMI 2650 cells in culture, enzyme-linked immunosorbent assay was used to investigate their TGF-? secretory capacity and the identification of the TGF-? isotype(s) involved, flow cytometry was used to demonstrate the presence of TGF-? receptors on the RPMI 2650 cells, and the quantitative real-time TaqMan PCR was used to measure TGF-? gene expression.Results TGF-?2 was identified as the main isotype secreted by the RPMI 2650 cells. HDM allergens and TNF-? increased both TGF-? gene expression and protein release from these cells, whereas grass pollen, IL-4, and IL-13 were without effect.Conclusions The RPMI 2650 nasal epithelial cell line represents a valid in vitro model to evaluate the regulation of TGF-? biology. In this system HDM allergens have stimulatory activity that is fundamentally different from that of grass pollen allergens, and the Th2 cytokines IL-4 and IL-13 are without effect. The ability of TNF-? to up-regulate both TGF-? gene expression and protein release indicates that mast cell–epithelial interactions concerning TGF-? are bi-directional and this may be fundamental to epithelial immunoregulation. The availability of a model system, such as the RPMI 2650 cells, will enable the early evaluation of future novel and targeted interventions directed toward the aberrant responses of upper airway structural cells
Allergic rhinitis: past, present and the future
No full textAllergic rhinitis represents a global health issue affecting between 10% to 25% of the world population, with increasing prevalence over the last decade. Although often trivialized by patients and doctors, allergic rhinitis is a significant cause of morbidity, in addition to its substantial economic impact. While allergic rhinitis is an inflammatory disorder of the upper airways, inflammation alone is insufficient to explain the chronic nature of the disease. An exciting concept which has recently emerged in asthma concerns the role of the bronchial epithelium as a key regulator of airway inflammatory and remodelling responses in asthma. It has been shown by our group that the disruption and alteration in the function of the lower airway epithelium in asthma leads to the generation of a variety of stimuli that lead to the restructuring of the airway wall. This raises interesting questions regarding a similar role for the upper airway epithelium in allergic rhinitis. This review aims to interpret past and current research into allergic rhinitis, and to address specific areas where future research is warranted, particularly in relation to the possibility of an altered upper airway epithelial phenotype in allergic rhinitis
Inflammatory mediators in naturally occurring rhinitis
No full textBackground: The mediators released during the allergic inflammatory reaction induce the clinical symptoms of the allergic disease and although there have been numerous studies investigating mediator release in allergen challenge models of allergic rhinitis very few have extended this approach to the study of natural disease.Objective: The aim of this investigation was therefore to measure mast cell and eosinophil mediator levels and indices of vascular permeability in naturally occurring rhinitis.Methods: Three groups of subjects were studied, normal non-rhinitics, seasonal allergic rhinitics in and out of the grass pollen season and perennial allergic rhinitics. Mediators were recovered using the technique of nasal lavage and the levels of tryptase, histamine, eosinophil cationic protein and albumin were determined. In addition, eosinophils were enumerated in nasal smears as an indices of underlying inflammation.Results: The levels of tryptase, eosinophil cationic protein and albumin were significantly higher in the lavage recovered from the symptomatic seasonal allergic rhinitics than when asymptomatic (P = 0.05, P = 0.003, P = 0.009, respectively). These levels of eosinophil cationic protein and albumin were also significantly higher than those of the normal non-rhinitics (P = 0.0008, P = 0.0.003, respectively). In the perennial allergic rhinitics the levels of tryptase, eosinophil cationic protein and albumin were higher than the normal non-rhinitics (P < 0.0001, P = 0.0003, P = 0.0001, respectively). The levels of tryptase and histamine were higher in the perennial allergic rhinitics than the seasonal allergic rhinitics (P = 0.0003, P = 0.006, respectively). These changes in mediator levels were accompanied by a significant influx of eosinophils into the nasal mucosa of both the symptomatic seasonal rhinitics, compared with asymptomatic (P = 0.04) and normal controls (P = 0.0006) and the perennial rhinitics compared to normal controls (P = 0.03).Conclusion: These results indicate that in both naturally occurring seasonal allergic rhinitis and perennial allergic rhinitis mast cell and eosinophil activation occurs and this is accompanied by an increase in vascular permeability. These measurements in lavage fluid provide a method of monitoring the mucosal cellular events in response to therapy.<br/
Nasal lavage fluid concentrations of eotaxin-1 (CCL11) in naturally occurring allergic rhinitis: relationship to disease activity, nasal luminal eosinophil influx, and plasma protein exudation
No full textBackground Eotaxin-1 (CCL11) is a CC chemokine whose nasal eosinophilic chemotactic activity in vivo and in vitro has been demonstrated primarily using nasal allergen challenge models. The extension of these challenge findings to the in vivo setting has been limited.Objective To obtain nasal lavage fluid from volunteers with perennial and seasonal (in- and out-of-season) allergic rhinitis (AR) and non-atopic non-rhinitic controls for the measurement of eotaxin-1 concentrations and to relate these findings to the symptomatic disease severity, the percentage of lavage eosinophils, and to ?2-macroglobulin (?2-MG) lavage concentrations, as a marker of vascular permeability and an index of airway inflammation.Methods Thirty-seven volunteers with AR (16 seasonal and 21 perennial) and 20 non-atopic non-rhinitic volunteers were recruited and phenotyped. Nasal lavage fluid was obtained by standardized protocol. The nasal lavage fluid concentrations of eotaxin and ?2-MG were measured by ELISA, and differential cell counts performed on cytospins.Results Eotaxin-1 nasal lavage fluid concentrations were significantly higher in both the perennial and seasonal (in-season) AR groups compared with the controls, and significantly related to the severity of symptom expression and to the percentage of lavage eosinophils. The lavage eosinophil counts were significantly higher in both the symptomatic rhinitis groups compared with the control groups and correlated with the lavage concentrations of ?2-MG. ?2-MG levels were significantly increased in seasonal (in-season) rhinitics compared with both non-atopic controls and seasonal (out-of-season) rhinitics. A significant correlation was observed between the levels of ?2-MG and levels of eotaxin in the symptomatic allergic rhinitic groups.Conclusions This study clearly demonstrates the relevance of eotaxin-1 to the pathogenesis of naturally occurring AR
Transforming growth factor-beta in allergic inflammatory disease of the upper airways: friend or foe?
No full textTGF-? is a multi-functional cytokine with a huge array of effects on a variety of cell types. It is rapidly emerging as a key major player in the way the airway epithelium behaves and its ability to repair itself. This is not only of relevance to allergic airway diseases such as asthma and allergic rhinitis, which are increasing in prevalence worldwide, but in many other diseases. The full impact any disruption of TGF-? signalling may have in the development and persistence of allergic inflammatory airway diseases is yet to be fully realized and remains the subject of ongoing research. There has been a recent revival of interest in the role of regulatory T cells in controlling allergic inflammation. Evidence is emerging of a significant contribution by TGF-? to this regulatory process. This review aims to summarize current knowledge relating to TGF-? in relation to allergic inflammatory upper airways disease, and attempts to clarify some of the discrepancies and inconsistencies in this area. It also considers the therapeutic implications of novel TGF-? therapy, including potential future applications in the treatment of nasal polyposis and reduction of post-operative scar tissue formation following endoscopic sinus surger
The allergen specificity of the late asthmatic reaction
No full textBACKGROUND: Allergen inhalation challenge in asthma may induce both early (EAR) and late (LAR) asthmatic reactions. The EAR is IgE and mast cell dependent. The mechanism of the LAR is less well defined and we have hypothesized may be allergen dependent. The aim of this study was to investigate the allergen specificity of the LAR to allergen inhalation in asthma.METHODS: In a randomized, double-blind, crossover design six asthmatic volunteers with dual sensitization to house dust mite (HDM) allergen and grass pollen (GP) allergen underwent inhalation allergen challenge with these separate allergens on two occasions separated by 14 days. Lung function changes were followed for 8-h postchallenge. Bronchial reactivity (histamine PC(20)) and airway inflammation, assessed by induced sputum differential cell count, were measured 24-h pre and postallergen challenge. The allergen inhalation challenges were matched to achieve the same magnitude of EAR.RESULTS: Despite comparable group mean EAR percent falls in FEV(1) (25.8% following GP and 28.0% following HDM (P = 0.917), the LAR was statistically greater on the HDM challenge day (13.0%vs 22.8% [P = 0.046]) and was associated with a significant airway eosinophil recruitment (mean (SD) of 5.4 (4.8)% to 22.1 (18.2)% (P = 0.028) that was not evident on the GP allergen challenge day.CONCLUSIONS: These findings identify the allergen specificity of the LAR and indicate that factors independent of IgE contribute to the LAR. Such findings have relevance both to the understanding of the allergen-induced airway responses in asthma and the need for homogeneity in inhaled-allergen challenge studies in asthma
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