Anti-inflammatory properties of montelukast, a leukotriene receptor antagonist in patients with asthma and nasal polyposis.

BACKGROUND: Leukotrienes, especially LTC4, are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways. Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase. OBJECTIVE: To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps, and determine its dependency on aspirin sensitization. METHODS: Twenty-four patients (7 women, 17 men; median age, 55.5 years) with nasal polyps and controlled asthma (n=12 with aspirin intolerance) were treated with 10 mg montelukast once daily for 6 weeks in a blinded, placebo-controlled fashion. The placebo phase was randomly assigned 4 weeks before (n=12) or after treatment (n=12). Symptom score, rhinoendoscopy, rhinomanometry, smears for eosinophils, and nasal lavages for the determination of different mediators were performed. RESULTS: Compared to placebo, there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment. Furthermore, reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment. CONCLUSION: Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma, with or without aspirin intolerance.

Effect of fluticasone on neuropeptides in nasal lavage in persistent allergic rhinitis.

OBJECTIVE: Recent guidelines reveal that allergic rhinitis impairs quality of life. Neuropeptides play a central role in allergy-related nasal inflammation. The objective of this study was to analyze the release of neuropeptides (substance P, neurokinin A, and vasoactive intestinal peptide) in nasal lavage and their modification by intranasal fluticasone propionate as an established therapy in patients with allergic rhinitis. METHODS: Eleven patients with proven allergic rhinitis induced by house dust mite were challenged before and after administration of fluticasone propionate nasal spray. Nasal lavage samples were collected after allergen challenge, and neuropeptides were measured using enzyme-linked immunosorbent assay. Values for histamine, protein, and human serum albumin were also recorded. Eight healthy individuals were included as nonatopic controls. RESULTS: The neuropeptides investigated were detectable in nasal lavage fluid in both patients and controls. Treatment with fluticasone propionate significantly decreased clinical response to allergen challenge (P < .01) compared with the controls and led to a decrease in values for substance P, neurokinin A, vasoactive intestinal peptide, histamine release, human serum albumin, and total protein after allergen challenge (P < .01). CONCLUSIONS: The demonstration of proinflammatory neuropeptides in NAL and suppression of their release after allergen challenge caused by a topical corticosteroid suggest a role for neuropeptides in allergic inflammation. Diminished release of neuropeptides induced b fluticasone propionate was accompanied by an improvement in the clinical symptoms of patients with persistent allergic rhinitis.

Effects of fexofenadine on inflammatory mediators in nasal lavage fluid in intermittent allergic rhinitis.

OBJECTIVE: Allergic rhinitis, a disease that impairs quality of life, is characterized by inflammation due to an allergic reaction. Fexofenadine is a second-generation histamine receptor blocker well known for its potent interaction with this inflammatory process. The main aim of this study was to further clarify the anti-inflammatory effects exerted by fexofenadine in patients with intermittent allergic rhinitis. METHODS: Twenty patients with intermittent allergic rhinitis due to birch and mugwort pollen were enrolled. Fexofenadine was administered once a day at a dose of 120 mg. Clinical improvement was assessed by a symptom score, and nasal airway flows were measured by anterior rhinomanometry at baseline and after 2 weeks of treatment with fexofenadine. Nasal smears were tested for eosinophils and nasal lavage fluid were examined for histamine, cysteinyl leukotrienes, soluble intercellular adhesion molecule-1, eosinophil cationic protein, and albumin by enzyme-linked immunosorbent assay. All the tests were performed during the pollen season. RESULTS: Fexofenadine induced a significant improvement in nasal and ocular symptoms (P < .001), nasal edema and secretion (P < .001), and nasal airway flow (P < .001). The clinical improvement was related to a significant reduction in all inflammatory mediators (P < .01 in all cases). CONCLUSION: This study demonstrates that fexofenadine is able to mediate significant changes in different nasal lavage markers from patients with intermittent allergic rhinitis. The changes observed in the markers analyzed in both nasal secretions and serum are attributable to the anti-inflammatory effects of fexofenadine in vivo.

Selective induction of nerve growth factor and brain-derived neurotrophic factor by LPS and allergen in dendritic cells.

BACKGROUND: Neurotrophins are produced by various cells upon different stimuli and participate in the initiation and regulation of inflammation in various diseases including allergy and asthma, but little is known about the production and control of neurotrophins by dendritic cells (DCs). The aim of this study was to assess whether DCs produce the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and whether inflammatory stimuli or allergens are able to induce the production of neurotrophic factors. METHODS: Monocyte-derived dendritic cells (MoDCs) were generated from different donors. The neurotrophins NGF and BDNF were demonstrated by RT-PCR, Western blotting, flow cytometry analysis and fluorescence microscopy. MoDCs were cultured and stimulated with lipopolysaccharide (LPS) or allergen for 24 h. The supernatants and cells were collected. Measurement for NGF and BDNF was performed by ELISA. RESULTS: DCs express mRNA for the neurotrophins NGF and BDNF. Proteins were detectable by Western blot, FACS analysis and fluorescence microscopy. LPS led to an up-regulation of BDNF, while NGF was unaffected. Cell lysates demonstrated an increased amount of BDNF after stimulation with LPS or allergen, while NGF was not affected significantly. CONCLUSIONS: DCs are a source of neurotrophins. LPS selectively regulates the production of BDNF. Allergen stimulation leads to an LPS-independent regulation. This contributes to a complex involvement of neurotrophins in allergic diseases.

Trigeminal nasal-specific neurons respond to nerve growth factor with substance-P biosynthesis.

BACKGROUND: Nerve growth factor (NGF) has been found to induce substance-P biosynthesis in large-diameter A-fibres vagal airway neurons. However, the effect of NGF on trigeminal neurons innervating the nasal mucosa of the mouse has not been investigated so far. OBJECTIVE: NGF has been implicated in allergic diseases by modulating sensory nerves. Therefore, the present study investigated the effect of NGF on neuropeptides expression such as substance-P and glutamate in nasal trigeminal neurons. METHODS: Using neuronal tracing in combination with double labelling immunohistochemistry the expression of substance-P, glutamate and neurofilament protein 68-kDa expression was examined in nasal-specific trigeminal neurons of BALB/c-mice. RESULTS: The numbers of Fast blue-labelled trigeminal neurons expressing substance-P were significantly increased after NGF exposure (NGF-treated ganglia: 16.4 +/- 0.6% vs. control: 7.0 +/- 0.4%, P

Correlation between immune and neuronal parameters and stress perception in allergic asthmatics.

BACKGROUND: Asthma is a chronic disease defined by airway inflammation, increased airway hyperresponsiveness and episodes of airway obstruction. Although there are abundant clinical and experimental data showing that stress may worsen asthma, the mechanisms linking stress to asthma are not well understood. By inducing a pro-inflammatory cytokine milieu, stress might enhance airway inflammation in bronchial asthma. We therefore investigated the correlation of stress perception and the cytokine profile of circulating lymphocytes in humans. METHODS: Allergic asthmatic patients and healthy controls were evaluated for perceived level of stress, demographic and lung function data. Whole blood cells were obtained and stimulated by mitogen to assess intracellular IL-4, IFN-gamma and TNF-alpha by flow cytometry. Neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were measured in serum. RESULTS: Asthmatic patients showed significantly higher percentages of TNF-alpha-producing T cells than healthy controls. Only in asthmatic patients was stress perception correlated with percentages of TNF-alpha-producing T cells and serum BDNF levels, while forced expiratory volume in 1 s (% predicted) was negatively correlated to BDNF. CONCLUSION: The results of our study support the hypothesis that stress deteriorates bronchial asthma by inducing a pro-inflammatory cytokine profile in allergic asthmatics. Stress management might provide a supplement therapy of allergic asthma.

In search of clinically relevant parameters to monitor successful omalizumab therapy in allergic asthma.

BACKGROUND: Omalizumab is approved as add-on therapy for the treatment of severe uncontrolled allergic asthma. Increase in quality of life and decrease of exacerbations and hospital admission, as well as immunmodulatory effects have been described with omalizumab therapy. However, to date there are few parameters to monitor success and to evaluate the individual advantage of this therapy for the patient. Furthermore, no reliable parameter to predict response to treatment exists so far. The aim of this study was to define an easily applicable parameter for response to treatment with omalizumab. METHOD: 43 patients with allergic asthma were treated with omalizumab at a dose of at least 0,016 mg/kg/IgE every 4 weeks. Before, and 12 weeks after initiation of therapy, bodyplethysmography including airway resistance was performed. Efficacy of treatment was judged by the attending physician on the basis of a five point chart. Furthermore, a differential blood count was performed before, and 12 weeks after initiation of treatment. Total and specific IgE against all relevant antigens were determined before start of therapy. RESULTS: Airway resistance in patients with response to treatment with omalizumab (responders) was significantly decreased in comparison to patients without clinical benefit (non-responder). The number of eosinophil granulocytes in the peripheral blood was decreased in both groups without significant difference. Response to therapy was associated with younger age and lower levels of specific IgE against the allergen with the highest sIgE-level (seasonal and perennial), but not with the sIgE level of the perennial allergens in general. CONCLUSION: Measurement of airway resistance might be an additional parameter for monitoring response to therapy with omalizumab. High specific IgE levels, for both perennial and concomitant seasonal allergens as well as increasing age, seem to predict less favorable treatment outcomes.

Efficacy and safety of formoterol delivered through the Novolizer, a novel dry powder inhaler (DPI) compared with a standard DPI in patients with moderate to severe asthma.

BACKGROUND & OBJECTIVE: Because of environmental concerns CFC-containing pressurised metered dose inhalers (pMDI) had to be replaced by dry powder inhalers (DPI). The Novolizer, a novel DPI has previously been shown to be as effective as the Turbuhaler in delivering budesonide. The objective of this study was to show non-inferiority of inhaled formoterol therapy delivered through the Novolizer compared to formoterol delivered through the Aerolizer in patients suffering from moderate to severe asthma. METHODS: In this double-blind, double-dummy, multicentre study 392 patients were randomised and received a dose of 12 microg formoterol twice daily for 4 weeks either through the Aerolizer or the Novolizer. FEV1 after 4 weeks of treatment was the primary variable. Secondary variables were FVC, PEF, consumption of short-acting; 2 adrenoceptor agonists, asthma symptoms, tolerability and safety. RESULTS: After 4 weeks of treatment, the mean trough FEV1 (95% CI) was 2.34 L (2.24-2.45) for the Novolizer and 2.31 L (2.21-2.41) for the Aerolizer. Non-inferiority was proven (p<0.0001, pre-defined; of 0.25 L). All secondary variables (incl. PEF) confirmed these findings. Treatment with both devices was safe and well tolerated. CONCLUSION: Inhalation of 12 microg formoterol twice daily via Novolizer was shown to be equally therapeutically effective compared to the inhalation via Aerolizer in the treatment of moderate to severe persistent asthma. Treatment via both inhalers was safe and well tolerated.

Differential activation of dendritic cells by nerve growth factor and brain-derived neurotrophic factor.

BACKGROUND: Neurotrophins are involved in inflammatory reactions influencing several cells in health and disease including allergy and asthma. Dendritic cells (DCs) play a major role in the induction of inflammatory processes with an increasing role in allergic diseases as well. OBJECTIVE: The aim of this study was to investigate the influence of neurotrophins on DC function. METHODS: Monocyte-derived dendritic cells were generated from allergic and non-allergic donors. Neurotrophin receptors were demonstrated by western blotting, flow cytometry and fluorescence microscopy. Activation of small GTPases was evaluated by pull-down assays. DCs were incubated with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and supernatants were collected for measurement of IL-4, IL-6, IL-10, IL-12p70, TNF-alpha and TGF-beta. RESULTS: Receptor proteins were detectable by western blot, fluorescence activated cell sorting analysis and fluorescence microscopy. Signalling after neurotrophin stimulation occurred in a ligand-specific pattern. NGF led to decreased RhoA and increased Rac activation, while BDNF affected RhoA and Rac activity in a reciprocal fashion. Cells of allergics released a significantly increased amount of IL-6, while for healthy subjects a significantly higher amount of IL-10 was found. CONCLUSION: These data indicate that DCs are activated by the neurotrophins NGF and BDNF by different pathways in a receptor-dependant manner. These cells then may initiate inflammatory responses based on allergic sensitization releasing preferred cytokines inducing tolerance or a T-helper type 2 response.

Cell type-specific regulation of brain-derived neurotrophic factor in states of allergic inflammation.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a molecule influencing neuronal proliferation and differentiation. In states of allergy, it may orchestrate inflammatory changes by linking the immune system with the nervous system. Because the precise regulation of gene transcription in mast cells MCs is not clear, the present studies assessed the gene regulation of BDNF in this inflammatory cell type. METHODS: Transcriptional expression of BDNF in human skin was studied in isolated cells using RT-PCR. In situ lesional MC BDNF protein expression was analysed by immunohistochemistry and related to the differential staining of MCs and functional effects of BDNF on HaCaT keratinocytes. RESULTS: BDNF mRNA expression was found in isolated human skin MCs, keratinocytes, and fibroblasts. Also, low levels were found in endothelial cells and melanocytes. BDNF protein expression was found in situ in lesional and non-lesional MCs. A significantly decreased expression of BDNF protein was found in atopic dermatitis lesional MCs when compared with control MC expression. Functional in vitro experiments demonstrated that a decrease in BDNF stimulation led to increased secretion rates for stem cell factor and IL-8 in HaCaT keratinocytes. CONCLUSION: The demonstration of a decreased level of BDNF gene transcription in lesional MCs points to a differential regulation of MC-released neutrotrophins in cutaneous allergic inflammation. Topically administered neurotrophin receptor-modulating compounds should be receptor target specific and not universally acting in diseases such as atopic dermatitis or allergic asthma.

Omalizumab decreased IgE-release and induced changes in cellular immunity in patients with allergic asthma.

BACKGROUND: Omalizumab, a recombinant monoclonal anti-immunoglobulin E (IgE) antibody, shows proven efficacy in the treatment of allergic diseases. A little is known about the immunological pathways affected by the decrease of circulating free IgE during omalizumab treatment. AIM OF THE STUDY: To investigate the immunological consequence of IgE withdrawal, we studied the influence of omalizumab on stimulated IgE-release of cultured peripheral blood mononuclear cells (PBMC) and on the relative number of lymphocytes in the peripheral blood (cellular immune status) in patients with allergic asthma. METHODS: Nineteen patients were enrolled and received omalizumab at a dose of at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks. PBMC were isolated from peripheral blood. Cells were cultured and stimulated with IL-4 (5 ng/ml) and CD40 ligand (1 microg/ml) for 10 days. IgE release was detected in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Cellular immune status was investigated by fluorescence-activated cell sorting. RESULTS: Omalizumab treatment induced significant inhibition of stimulated IgE release (median 1.38-0 ng/ml vs. 1.64-2.0 ng/ml in placebo group, P<0.05). B-lymphocyte counts were also significantly lower in the omalizumab group compared with placebo after 12 weeks of treatment (median 18.2-15.6% lymphocytes vs 12.7-13.7% lymphocytes after placebo, P<0.01). There were no significant differences in the other lymphocyte subpopulations between the groups. CONCLUSIONS: These findings provide evidence of immunological influences of omalizumab treatment, leading to a downregulation of IgE secretion and decrease of lymphocyte subpopulations (B-cells) indicating their anti-inflammatory potency.

Omalizumab inhibits allergen challenge-induced nasal response.

Elevated serum levels of antigen-specific immunoglobulin (Ig)E are often associated with allergic respiratory diseases. This parallel-group, randomised, double-blind, placebo-controlled trial was designed to study the influence of omalizumab on the early nasal response to allergen challenge reflected by symptom score and inflammatory marker levels in nasal lavage fluid (NAL). A total of 23 patients with allergic rhinitis took part in the study, 11 were given placebo and omalizumab was administered subcutaneously in 12. Omalizumab or placebo were given at 2- or 4-week intervals based on a patient's body weight and IgE levels to a total dose of 0.016 mg x kg(-1) x IgE(-1) (IU x mL(-1)) every 4 weeks. Compared to placebo, 16 weeks of treatment with omalizumab significantly inhibited allergen challenge-induced nasal symptoms (median symptom score 7.0-0.5 versus 7.0-7.0) and inhibited the increase of human serum albumin (median 15.3-0.12 mg x mL(-1) versus 8.2-19.7 mg x mL(-1)) in the NAL after allergen challenge. Treatment with omalizumab induced a significant decrease in tumour necrosis factor-alpha levels in basal NAL, but no change was seen for histamine. These results indicate that subcutaneously administered monoclonal anti-immunoglobulin-E antibody, omalizumab, inhibits the nasal responses to allergen challenge of patients with allergic rhinitis. Omalizumab may provide a new strategy for the treatment of allergic rhinitis.

Heparin, derived from the mast cells of human lungs is responsible for the generation of kinins in allergic reactions due to the activation of the contact system.

BACKGROUND: In a recent study mast cell heparin proteoglycan (HepPG) of a cell line derived from a mouse mastocytoma was isolated. Glycosaminoglycans proved to be an initiating surface for starting contact activation and could explain kinin generation present in allergic reactions. It is the aim of the present study to prove that HepPG or glycosaminoglycan derived from human mast cells is also capable of acting as a physiologic macromolecule and to induce contact activation. METHODS: HepPG molecules were isolated by anionic column chromatography. Their ability to accelerate reciprocal activation of factor XII was investigated by spectrophotometry. The anticoagulant effect was demonstrated by an increase in partial thromboplastin time. HPLC was performed to correlate these effects with molecular weight (MW). RESULTS: The isolated heparin showed high contact-activating and anticoagulant potency. Both actions were suppressed by incubation with heparinase I. The maximum contact activation peak appeared at a lower MW than the anticoagulant effect. CONCLUSION: These in vitro results explain the results of in vivo allergen challenge studies where a high degree of kinin generation occurs. Heparin derived from human mast cells therefore seems to represent the physiological macromolecule capable of activating the contact system and could be a missing link between cellular and humoral responses in allergic reactions.

Activation of the specific neurotrophin receptors TrkA, TrkB and TrkC influences the function of eosinophils.

BACKGROUND: Recent studies have shown that nerve growth factor (NGF) can act on several immune cells as well as residential cells. But little is known about their role in modulating eosinophil function via activation of high-affinity receptors. OBJECTIVES: The aim of this study was to assess whether eosinophils express functional receptors and if their function is influenced by NGF, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). METHODS: Eosinophils were purified by negative immunoselection (purity > 96%). High-affinity neurotrophin receptors were demonstrated by reverse transcription polymerase chain reaction, western blotting and flow-cytometry analysis. Functionality of receptors was demonstrated by receptor phosphorylation after ligand binding. Eosinophils were incubated with NGF, BDNF and NT-3, and cells and supernatants were collected for measurement of the mediators IL-4, IL-5, IL-8, transforming growth factor (TGF)-beta1, eosinophil cationic protein (ECP), eosinophil protein X (EPX) as well as eosinophil viability. RESULTS: Eosinophils expressed mRNA for neurotrophin receptors. Proteins were detectable by western blot and fluorescent-activated cell sorter analysis. The receptors were phosphorylated after stimulation with neurotrophins. After NGF stimulation, a significant increase in IL-4 was detectable. BDNF and NT-3 stimulation led to a significant increase in EPX. Eosinophil viability was not influenced. CONCLUSIONS: Eosinophils express the functionally active receptors TrkA, TrkB and TrkC. Receptor activation stimulates eosinophils. This might be an additional pathway regulating inflammatory responses in allergic reactions.

The influence of inhalative corticosteroids on circulating Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Neurotrophin-3 in allergic asthmatics.

BACKGROUND: The neurotrophins Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin (NT)-3 are produced, stored and released by various immunological cells. The influence of NTs upon the function of these cells is described. Elevated plasma levels were found in inflammatory, autoimmune and allergic diseases with the highest levels in allergic asthma. A connection between bronchial hyper-responsiveness and serum levels has been reported. OBJECTIVE: Little is known about the influence of treatment with inhaled corticosteroids (ICS) on serum NT levels and their influence on the asthmatic state. METHODS: Eighty-seven volunteers were studied. Thirty-eight were stable allergic asthmatics with constant ICS doses, 29 were asthmatics not receiving anti-asthmatic treatment and 20 were age- and sex-matched healthy controls. Demographic and lung function data were evaluated. NT serum levels were determined by ELISA. RESULTS: NGF and BDNF levels were significantly increased in untreated asthmatics compared to the control and the treated group, while NT-3 demonstrated significantly higher levels in treated asthmatics compared to healthy controls. After stabilization of untreated subjects with ICS, the NT levels decreased significantly. CONCLUSIONS: These results suggest that NTs participate in allergic inflammation and asthma. Effective treatment leads to a decrease of circulating neurotrophic factors.

Substance P induced histamine release from nasal mucosa of subjects with and without allergic rhinitis.

OBJECTIVE AND DESIGN: There is evidence that substance P (SP) is involved in events related to allergic and nonallergic rhinitis. Furthermore, some effects of SP seem to be greater in subjects suffering from allergic rhinitis than in nonallergic subjects. To investigate if these effects may be partly mediated by histamine release (HR) we studied the influence of SP on HR from nasal mucosa of subjects with and without allergic rhinitis using an in vitro organ culture system. SUBJECTS: Nasal mucosa of the inferior turbinate was obtained from ten patients suffering from allergic rhinitis and eighteen non-allergic subjects receiving surgical therapy for nasal obstruction. METHODS: Tissue samples of nasal mucosa were stimulated with 10(-5) M SP or with 10(-5) M Ca-ionophore A23187 for 120 minutes, and the histamine content was determined in the culture supernatant. RESULTS: Both SP and Ca-ionophore A23187, caused a significantly higher HR from the samples of the non-allergic group (p < 0.01) compared to baseline controls (spontaneous release). The same effect was seen in the allergic group (p < 0.01 and p = 0.036). Comparing the increase in HR from allergic and non-allergic mucosa, in allergics the HR stimulated by SP was significantly higher (p = 0.031), whereas Ca-ionophore A23187 did not show this effect. CONCLUSION: These findings suggest a role of SP in inducing release of histamine from human nasal mucosa, thereby influencing physiologic and pathophysiologic nasal conditions, especially in allergic inflammatory processes.

Efficacy, safety, and acceptance of beclomethasone dipropionate administered via a new dry powder Inhaler or a standard CFC metered-dose inhaler in asthma patients.

BACKGROUND/OBJECTIVES: The mechanical aerosol generator, MAGhaler, is a new chlorofluorocarbon-free inhalation device. The objective of this trial was to show equivalent efficacy and safety of beclomethasone dipropionate (BDP) delivered via the MAGhaler and the metered-dose inhaler (MDI) in patients with mild to moderate bronchial asthma. Moreover, user-friendliness and acceptance of the two devices were compared. METHODS: This was a double-blind, reference-controlled, 12-week trial in 171 patients with asthma receiving BDP (1,000 microg/day) delivered via either the MAGhaler or the conventional MDI. Respiratory function parameters, clinical symptoms, concomitant intake of salbutamol or fenoterol, adverse events (AEs), laboratory values, and concomitant medications and diseases were recorded. The primary efficacy parameter was mean forced expiratory volume in 1 s (FEV1), measured after 4, 8, and 12 weeks of therapy. RESULTS: The equivalence of the two devices was confirmed (p = 0.003) on the basis of the ratios of the mean FEV1 in weeks 4 to 12. Mean (+/- SD) FEV1 (MAGhaler was 2.24 +/- 0.60 l (baseline), 2.61 +/- 0.90 litres (week 4), and 2.62 +/- 0.87 litres (weeks 4-12). Mean FEV1 (MDI) was 2.28 +/- 0.59 litres (baseline), 2.53 +/- 0.82 litres (week 4), and 2.56 +/- 0.77 litres (weeks 4-12). In total, 33 AEs occurred in 26 (30.2%) patients (MAGhaler) and 51 AEs in 36 (42.4%) patients (MDI). Most of the AEs were of mild or moderate intensity. The relationship to treatment could not be excluded for 11 AEs in 11 patients (MAGhaler) and 23 AEs in 18 patients (MDI). Three serious AEs, all unrelated to treatment, occurred in 3 patients (MAGhaler: 2, MDI: 1). There were no clinically relevant changes in other safety parameters. Most patients either preferred the MAGhaler or rated the two devices as equally acceptable. CONCLUSION: The new MAGhaler was equivalent to the standard MDI in terms of the safety and efficacy of BDP. The improved user-friendliness and acceptance of the MAGhaler over the conventional MDI represent an important advance in the clinical management of bronchial asthma.

The production, storage and release of the neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 by human peripheral eosinophils in allergics and non-allergics.

BACKGROUND: Recent studies have shown that neurotrophins are produced by and can act on several immune-inflammatory cells. The origin of circulating as well as local neurotrophins is unknown. OBJECTIVES: The aim of this study was to assess whether eosinophils of allergic and non-allergic donors produce, store and release the neurotrophic factors NGF, BDNF and NT-3. METHODS: Eosinophils were purified by negative immunoselection (purity > 96%) from allergic asthmatics and non-allergic donors (25 to 53 years). The presence of mRNA for neurotrophic factors was evaluated by reverse transcription PCR. Specificity was demonstrated by cloning products and sequencing. Stored NGF, BDNF and NT-3 was demonstrated by Western-blotting and flow cytometry. Eosinophils were incubated and supernatants were collected for measurement of neurotrophic factors after cell stimulation with PAF. Neurotrophin content in eosinophil lysates was determined by ELISA. RESULTS: Eosinophils demonstrate mRNA for neurotrophins. Proteins were detectable by Western blot and FACS analysis. Neurotrophins were found in the eosinophil lysates at different amounts comparing allergic and non-allergic donors. Cell stimulation with PAF (10-8-10-5 M) after priming with GM-CSF leads to a dose-dependant release of NGF and BDNF. CONCLUSIONS: Eosinophils store, produce and release NGF, BDNF and NT-3. They are a possible source of elevated neurotrophin levels found in allergy and asthma.

Omalizumab provides long-term control in patients with moderate-to-severe allergic asthma.

The ability of omalizumab, an anti-immnoglobulin-E agent, to maintain long-term disease control in patients with moderate-to-severe allergic asthma was investigated in a 24-week double-blind extension to a 28-week core trial. During the extension, 483 of the initial 546 patients were maintained on randomised treatment and the lowest sustainable dose of beclomethasone dipropionate (BDP) as established during the steroid-reduction phase of the core trial. The use of concomitant asthma medication was permitted and investigators were allowed to adjust the BDP dose or switch patients from BDP to other asthma medications if deemed necessary. More omalizumab-treated patients (33.5%) than placebo-treated patients (13.5%) were able to complete the extension period without requiring inhaled corticosteroid treatment. The mean BDP equivalent dose throughout the extension was lower in the omalizumab group (25 microg x day(-1)) than in the placebo group (43 microg x day(-1)). Disease control was sustained in 76% of omalizumab patients compared with 59.4% of placebo patients free from an asthma exacerbation during the extension period. Compared with placebo, fewer patients in the omalizumab group used other concomitant asthma medication during the extension. Treatment with omalizumab was well tolerated and the incidence of adverse events was similar between groups. In conclusion, these results suggest that omalizumab is a promising new agent for the long-term control of allergic asthma.